The recent development of selective and highly potent nonpeptide antagonists for peptide receptors has constituted a major breakthrough in the field of neuropeptide research. Following the discovery of the first nonpeptide antagonists for peptide receptors ten years ago, numerous other antagonists have been developed for most neuropeptide families. These new, metabolically stable compounds, orally active and capable of crossing the blood brain barrier, offer clear advantages over the previously available peptide antagonists. Nonpeptide antagonists have provided valuable tools to investigate peptide receptors at the molecular, pharmacological and anatomical levels, and have considerably advanced our understanding of the pathophysiological roles of peptides in the CNS and periphery. Evidence from animal and clinical studies suggests that nonpeptide antagonists binding to peptide receptors could be useful for the treatment of disease states associated with high levels of neuropeptides.

Over the past two decades, a large number of novel peptides have been identified in the CNS, many of which fulfill the criteria to be considered potential neurotransmitters. In addition, numerous receptors and receptor subtypes that recognize peptide ligands have been described, based on pharmacological studies. The recent molecular cloning and sequencing of many neuropeptide receptor genes in various species has confirmed and extended the existing classifications. All neuropeptide receptors described so far belong to the G-protein-coupled receptor super-family, characterized by seven transmembrane spanning regions. Despite the great amount of works dedicated to neuropeptides in the past years, our understanding of their role in physiology and disease has been limited by the lack of suitable potent and selective receptor antagonists. Indeed, knowledge about the functional role of classical neurotransmitters has been mostly based on pharmacological studies using specific high-affinity receptor antagonists; until recently, such drugs were not available for neuropeptides, with the exception of opioid receptor antagonists such as naloxone.

Drugs with antagonistic actions for neuropeptide receptors can be classified as either peptides or nonpeptides. Antagonists of a peptide nature are available for several neuropeptides and have been widely used experimentally. However, these antagonists have several drawbacks, including high biodegradability, which precludes oral administration and implies a relatively short duration of action; high molecular weight and thus expensive synthesis; and in general, failure to cross the blood-brain barrier. Other limitations frequently encountered when using peptide antagonists include lack of selectivity for specific receptor subtypes and intrinsic agonistic properties, which contribute to their limited therapeutic and research potential. One of the most exciting advancements in the field of peptide research has been the development of nonpeptide compounds that act as selective antagonists of neuropeptide receptors. Following the discovery of the first nonpeptide antagonist of cholecystokinin (CCK) receptors in 19861^,2 (^{Box 1}), many other such compounds have been developed, including nonpeptide antagonists specific for tachykinins (substance P and related neurokinins A and B), angiotensin II, neurotensin, vasopressin, oxytocin, endothelin, neuropeptide Y (NPY), bradykinin and corticotropin releasing factor (CRF). In this article we will address the recent developments in nonpeptide antagonists for neuropeptide receptors, with a particular focus on their CNS actions.

Two different strategies have been used in the discovery of nonpeptide antagonists of peptide receptors: 1) random screening of large compound libraries, using different biological assays, most frequently radioligand binding; and 2) rational drug-design strategies, i.e., development of a lead compound on the basis of a known peptide ligand. Although several nonpeptide antagonists have been obtained using the rational design approach, including ligands for CCK3 and NPY⁴, the file screening approach, based initially on natural compounds or, most recently, on synthetic chemicals, has proved most effective. For instance, SR48692, the first potent and selective nonpeptide antagonist of neurotensin receptors, was obtained by optimization of a lead compound discovered by random screening of several thousand chemicals⁵. Moreover, the majority of the nonpeptide tachykinin NK-₁ and NK₂ receptor antagonists available today arose from targeted screening of large compound libraries using a radioligand binding assay as the primary screen⁶, whereas rational drug-design strategies have proved useful for the synthesis of nonpeptide tachykinin antagonists only in limited cases (^{Box 2}). Increasing knowledge concerning ligand-receptor interactions will likely facilitate the rational design of novel nonpeptide antagonists with high affinity for peptide receptors.

Nonpeptide receptor antagonists are chemically unrelated to the corresponding endogenous agonists, and their mechanism of action is not clear. Within the past few years, however, the molecular interaction of nonpeptide antagonists with their receptors has started to be characterized using applied molecular biology approaches, including receptor expression and site-directed mutagenesis. As most nonpeptide antagonists act as classical competitive ligands, it was initially expected that nonpeptide antagonists would share at least a major part of their binding site with the corresponding peptide agonist. However, it has become increasingly clear that this is seldom the case. The use of antagonist-derived radioligands as well as mutational analysis of receptors has suggested the existence of distinct agonist and antagonist binding domains on receptors for tachykinins7^–10, CCK^11,12, angiotensin^13,14, opioids¹⁵, neurotensin¹⁶ and vasopressin¹⁷.

The use of receptor mutagenesis to map binding sites has revealed that most peptide agonists interact primarily with residues located in the exterior part of the receptor, and contact points are frequently found in the N-terminal region (Fig. 1). In contrast, nonpeptide antagonists interact with residues located more deeply in the main ligand binding pocket, between the seven transmembrane segments¹⁸. Consequently, it has proven extremely difficult to identify point mutations which alter both peptide agonist and nonpeptide antagonist binding. In order to explain these observations, Schwartz and co-workers¹⁸ have proposed an allosteric receptor model in which the ligands exert their effect by selecting and stabilizing preformed receptor conformations and thus shifting the equilibrium towards either an active or an inactive state. Hence, nonpeptide antagonists bind to the inactive form of the receptor and shift the equilibrium away from the conformation required for agonist binding and receptor activation. The binding sites for agonists and antagonists can be different or overlap, depending on the peptide receptor system. In this receptor model, there is no requirement for an overlap in binding sites between competitive ligands, as the peptide agonist and nonpeptide antagonist act as allosteric competitive ligands by binding in a mutually exclusive fashion to sites occurring in different conformations of the receptor.

Nonpeptide antagonists are currently being developed not only as potential drugs but also as pharmacological and physiological tools. Indeed, the existence of receptor subtypes for several neuropeptides has been established on pharmacological grounds using selective nonpeptide antagonists. For example, the discovery of nonpeptide antagonists which were highly selective for either peripheral or brain CCK receptors provided support for the existence of two subtypes of CCK receptors (Box 1). CCK_A receptors are characterized by high affinity for the antagonist L364718 (Ref. ²), whereas CCK_B receptors show high affinity for the antagonist L365260 (Ref. ¹⁹). Similarly, the development of nonpeptide angiotensin II receptor antagonists led to the discovery of two pharmacologically and functionally distinct angiotensin receptors (for review, see Ref. ²⁰). The AT₁ receptor binds the nonpeptide antagonist losartan (DuP753) with high affinity, whereas the AT₂ receptor is insensitive to losartan but shows high affinity for the antagonist PD123319.

Autoradiography with nonpeptide antagonist as radioligands or to displace agonist labeling has proved particularly useful in studying the distribution of peptide receptors in the CNS and the periphery and to discriminate between different receptor subtypes. For instance, binding of radiolabeled angiotensin II in the presence of selective nonpeptide antagonists revealed the presence of both AT₁ and AT₂ receptors in the brain²¹. The central distribution of AT₁ receptors is in agreement with their role in mediating all the major physiological actions of angiotensin II, including regulation of blood pressure and water balance²⁰. AT₂ receptors are abundant during fetal life and in discrete brain regions but their function remains unclear²².

Selective nonpeptide antagonist were also used to study the brain distribution of CCK_A receptors²³, which had been previously identified only in the gastrointestinal tract. In autoradiographic experiments, CCK_A receptors were identified by displacing ¹²⁵I-CCK-8 binding with the CCK_A antagonist L365031, and by direct labeling with the antagonist ligand ³H-L364718. CCK_A receptors were observed in discrete areas of the rat CNS, including the area postrema and nucleus tractus solitarius, two regions receiving rich vagal input. This localization is in agreement with the role of CCK_A receptors in the regulation of satiety, through the processing of afferent vagal information from the periphery²⁴.

Radiolabeled ligands derived from nonpeptide antagonists represent useful tools to characterize the different affinity states of neuropeptide receptors. By comparing results obtained from binding of agonist and antagonist radioligands, pancreatic CCK_A receptors were shown to exist in three different affinity states for the agonist CCK-8; the agonist ligand (¹²⁵I-CCK-8) identified the high- and the low-affinity states, while the antagonist ligand (³H-L364718) bound to the low-affinity state and to a previously unidentified very-low-affinity state which represents 80% of the receptors25. The CCK_B/gastrin receptor also exists in a very low affinity state, detected by the nonpeptide antagonist ³H-L365260, which recognized a significantly higher number of receptors in the brain and gastric cells than the agonist ¹²⁵I-CCK-8 (Ref. ²⁶). The ability of radiolabeled nonpeptide antagonists to recognize a larger number of receptors, characterized by low affinity for the agonist, than agonist-derived radioligands, appears to be a common phenomenon. In the guinea-pig brain, the number of binding sites labeled by the nonpeptide neurotensin antagonist radioligand, ³H-SR48692, exceeded by 20-fold the number of receptors labeled with the agonist ¹²⁵I-neurotensin (Ref. ²⁷). The binding sites detected by ³H-SR48692 were characterized by a low affinity for neurotensin and were insensitive to guanyl nucleotides. These data indicate that the majority (96%) of neurotensin receptors in the guinea-pig brain exists in a low affinity state for the peptide, representing the G-protein uncoupled form of the receptor, whereas only a small proportion (4%) binds neurotensin with a high affinity. These data, together with current hypotheses on the molecular interactions of ligands with their receptors, suggest that radiolabeled agonists and antagonists bind to two complementary populations of receptor conformations¹⁸. Antagonists bind with high affinity to the G-protein-uncoupled receptors, whereas agonists bind with high affinity to the G-protein-coupled form, but they also bind with low affinity to the G-protein uncoupled form labeled by antagonists.

In contrast to the endogenous peptide ligands, nonpeptide antagonists often show substantial differences in affinity among species, suggesting that during evolution, peptide receptors have undergone mutations that do not affect the binding of the natural peptide, but frequently modify the nonpeptide antagonist binding sites. The species-related differences in antagonist binding affinity often reflect differences in the primary structure of the receptors. Do these differences represent distinct receptor subtypes or species variants of the same receptor? This question is important not only to clarify the definition of receptor subtypes, but becomes particularly relevant when selecting animal models to test drugs with therapeutic potential.

This concept can be illustrated with the example of tachykinin NK₁ receptors, which exhibit profound pharmacological differences among species in their recognition of nonpeptide antagonists. CP96345 has a much lower affinity for rat and mouse NK₁ receptors than for NK₁ receptors of most species studied, including human, guinea pig and rabbit. The reverse selectivity has been reported for RP67580, which has higher affinity for rat and mouse NK₁ receptors. Amino acid sequence comparison of the human and rat NK₁ receptor reveals only 22 divergent residues among 407. Analysis of mutant receptors in which divergent residues in the human NK₁ receptor were substituted by the rat homologues revealed that substitution of two rat residues at positions 116 and 290 within the transmembrane domain into the human NK₁ receptor are sufficient to reproduce the antagonist affinities of the rat receptor9^,28. Further studies have shown that the species selectivity of several other chemically distinct tachykinin nonpeptide antagonists also depends on the same amino acid residues²⁹. Interestingly, guinea pig and mouse NK₁ receptors have the same residues at positions 116 and 290 as the human and rat NK₁ receptors, respectively, extending to other species the importance of these residues as determinants of the differential affinities of antagonist binding. Thus, the species selectivity of nonpeptide antagonists result from the existence of species variants of the NK₁ receptor, rather than from different receptor subtypes. Similar inter-species differences in the affinity of nonpeptide antagonists also exist for NK₂ and NK₃ receptors^30,31.

The discovery of nonpeptide antagonists for CCK_B receptors has also led to the observation of differences in antagonist binding affinity between species. Although canine and human CCK_B receptors share ~90% amino acid identity and have similar agonist binding affinity, they exhibit opposite rank orders of affinity for two nonpeptide CCK antagonists: L365260 shows selectivity for the human receptor, whereas L364718 displays a higher affinity for the dog CCK receptor. Mutational analysis of the CCK_B receptor demonstrated that antagonist affinities can be altered dramatically by a single amino acid substitution, which in turn explain species-related differences¹¹. The replacement of valine 319 in the sixth transmembrane region of the human receptor with the corresponding amino acid in the canine receptor, leucine, decreases the affinity of L365260 and increases the affinity of L364718 to the values seen in the canine receptor. Conversely, substitution of Leu355 to valine in the canine receptor results in antagonist affinities that resemble those observed in the human receptor. It is interesting to note that these mutations do not alter the affinity of the endogenous peptide ligand, CCK. These results support the concept that differences in amino acid sequence between these species are simply due to a species-specific polymorphism of the same receptor subtype and do not represent novel CCK receptor subtypes.

These studies emphasize the need for species-appropriate models for the screening of antagonists in drug development. Animals used in the screening of nonpeptide antagonists for potential clinical use in humans should have receptors with pharmacological profiles similar to the human homologues. For instance, screening the nonpeptide antagonists CP96345 and RP67580 on rat and mouse NK₁ receptors (which have marked affinity differences for these antagonist compared to the human NK₁ receptor) would poorly predict pharmacological action in man, whereas guinea pig or rabbit NK₁ receptors would be suitable models³⁰. This is of particular importance when studying the antinociceptive effects of NK₁ antagonists, since most of the animal models of pain classically used employ mice or rats.

In order to help in defining receptor function, antagonists must have high specificity in vitro and in vivo and should be devoid of intrinsic or partial agonist activity. As mentioned previously, most peptide antagonists do not meet these requirements, explaining why the advent of nonpeptide receptor antagonists represented a significant progress in the study of the physiological role of neuropeptides.

Recent studies with nonpeptide antagonists of CCK receptors suggest that endogenous CCK plays a role in anxiety, satiety, pain perception, and certain dopamine-mediated behaviors (for review, see Ref. 24). In particular, endogenous CCK modulates dopaminergic transmission in the nucleus accumbens, which is considered the major neural substrate for the reinforcing properties of drugs of abuse. Converging evidence suggests that endogenous activation of CCK_B receptors exerts an inhibitory influence on drug reward and locomotor activation, whereas CCK_A receptors facilitate these behaviors³². Selective CCK_B antagonists such as L365260 and CI988 (formerly PD134308) potentiated the rewarding effects of amphetamine and morphine in the conditioned place preference paradigm in rats^33,34. Conversely, pretreatment with the CCK_A antagonist devazepide blocked morphine-induced place preference. The effects of endogenous CCK are more readily observed when the dopaminergic systems have been previously stimulated, whereas the role of the peptide under basal activity is more difficult to establish. Several studies have failed to find significant effects on dopamine-related behaviors after administration of CCK_A or CCK_B antagonists alone^24,34. It is probable that special behavioral paradigms may be needed to detect changes due to CCK antagonists, which specifically enhance the activity of dopaminergic neurons to a level likely to induce release of endogenous CCK.

Studies with nonpeptide CCK_B receptor antagonists have also indicated that endogenous CCK acts as an anxiogenic molecule, since its blockade by the CCK_B antagonists PD134308 and PD135158 induced potent anxiolytic effects in various animal models³. In contrast to benzodiazepines, CCK_B antagonists did not induce sedation and when administered on a chronic basis, did not induce tolerance nor withdrawal symptoms. Furthermore, CCK_B antagonists counteracted withdrawal anxiety induced by diazepam. Several other CCK_B antagonists (L365260, LY262691, LY262684, LY247348, and LY288513), have also demonstrated anxiolytic activity in animal studies. These results strongly support the therapeutic potential of CCK_B nonpeptide antagonists as anxiolytic agents and suggest that such compounds could be more selective and free of side effects when compared to benzodiazepines.

Exogenous CCK induces satiety and decreases food intake in both animals and humans; before selective antagonists for CCK_A and CCK_B receptors became available, it was not known which receptor subtype mediated this response. Numerous studies have now established that the CCK-induced reduction in food intake is blocked by CCK_A, but not CCK_B, receptor antagonists²⁴. Studies with the CCK_A antagonist devazepide, have also provided strong evidence for the role of endogenous CCK in the regulation of feeding. Systemic administration of devazepide increased food intake in rats and mice²⁴, and clinical data suggest that CCK could also act as a satiety signal in humans³⁵. The CCK_B antagonist L365260 has also been reported to increase food intake and to postpone the onset of satiety in rats³⁶, suggesting that in some situations, endogenous CCK may act on CCK_B receptors to induce postprandial satiety. In addition, recent findings with selective CCK_B receptor antagonists have revealed that endogenous CCK is implicated in the perception of pain (for review, see Ref. ³⁷). Specifically, CCK_B receptor antagonists such as L365260 and CI988 strongly enhanced morphine analgesia and prevented the development of tolerance to the analgesic effect of morphine in rats^38–40. These data raise the possibility that CCK_B antagonists, alone or in combination with opiates, may be useful in the management of chronic pain.

Thanks to the development of nonpeptide antagonists highly selective for angiotensin receptor subtypes, it was possible to describe novel physiological actions for central AT₁ receptors, particularly concerning their involvement in the modulation of neurotransmitter systems. In the human brain, AT₁ receptors are associated with dopaminergic neurons in the substantia nigra and their terminals in the striatum. Accordingly, angiotensin II increased dopamine turnover in the striatum, an effect which was completely blocked by the AT₁- selective antagonist, losartan⁴¹. Administration of losartan alone led to significant depression of DOPAC levels, suggesting that dopamine release is under the tonic facilitatory influence of endogenous angiotensin II. Using similar physiological approaches, AT₁ receptors have also been implicated in the central regulation of blood pressure and vasopressin release, through modulation of adrenaline and noradrenaline transmission, respectively.

Much of the current interest in the new nonpeptide neurotensin antagonist SR48692 has been focused on investigating the role of endogenous neurotensin in the modulation of dopaminergic systems. Data obtained with this antagonist indicate that endogenous neurotensin can exert both inhibitory and excitatory effects on dopaminergic activity, confirming the dual action of exogenous neurotensin observed in previous studies following central administration of the peptide. Thus, administration of SR48692 together with a subeffective dose of methamphetamine resulted in a significant increase in locomotion and rearing as well as in the release of dopamine in the nucleus accumbens⁴². SR48692 also potentiated dopamine efflux in the nucleus accumbens evoked by the concomitant administration of haloperidol and electrical stimulation of the medial forebrain bundle; when administered alone, SR48692 did not affect spontaneous dopamine release⁴³. By contrast, SR48692 reduced yawning and turning behavior induced by dopaminergic agonists⁴⁴, indicating that neurotensin facilitates the expression of certain behaviors associated with dopamine receptor stimulation. These findings also suggest that the modulatory role of endogenous neurotensin may require previous stimulation of dopaminergic neurons.

The availability of SR48692 has also allowed examination of the effects of endogenous neurotensin in the modulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic administration of SR48692 at the level of the paraventricular nucleus of the hypothalamus antagonized stress-induced release of ACTH and corticosterone and reduced CRF mRNA levels in the paraventricular nucleus, suggesting that endogenous neurotensin plays a tonic stimulatory role on HPA axis activity⁴⁵. In view of increasing evidence supporting a link between hyperactivity of the HPA axis and depressive disorders⁴⁶, these findings raise the interesting possibility that neurotensin antagonists might be useful in the treatment of affective disorders.

In agreement with the role of tachykinins in pain transmission and neurogenic inflammation, NK₁, receptor antagonists, such as CP96345 (Ref. ⁴⁷) and RP67580 (Ref. ⁴⁸), have been shown to possess antinociceptive activity in classical analgesic tests in mice and rats. These findings suggest the utility of tachykinin antagonists as a novel class of analgesic and anti-inflammatory agents. Moreover, a role for tachykinins in the pathogenesis of asthma has been postulated, indicating that tachykinin antagonists could be useful in the treatment of this disease.

Several nonpeptide antagonists of peptide receptors offer hope as novel therapeutic agents, particularly in the context of clinical findings suggesting that neuropeptides may be hypersecreted in certain pathological states. Following are some examples illustrating the potential use of nonpeptide antagonists in therapy.

In the ten years since the report of the discovery of the first nonpeptide antagonist of a non-opioid peptide receptor, more than 100 potent and selective nonpeptide antagonists for several peptides have been developed. The entire neuropeptide field has seen a remarkable advancement, largely fuelled by the availability of effective antagonists with which to study the physiological functions of peptides. This review has highlighted some of the common concepts on nonpeptide antagonists that have emerged during the past few years.

One of the most important contributions coming from the discovery of nonpeptide antagonists has been the characterization of the molecular interactions of nonpeptide ligands with peptide receptors. Pharmacological studies using nonpeptide receptor antagonist-derived ligands coupled with molecular biology techniques have considerably increased our knowledge on ligand-receptor interactions. Understanding the molecular interactions responsible for nonpeptide antagonist binding should provide a rational basis for the future development of more potent and selective antagonists for peptide receptors and for related G-protein-coupled receptors.

The use of nonpeptide antagonists to probe the physiological and pathophysiological actions of peptide receptors and their possible therapeutic relevance has proved particularly rewarding. Increasing evidence points out to the role of endogenous neuropeptides as modulators of brain neurotransmitter systems, suggesting the potential therapeutic application of these antagonists in neuropsychiatric disorders associated with altered neurotransmitter activity.

In spite of the great number of potent and selective neuropeptide antagonists available, it still remains difficult to attribute specific functions to endogenous peptides under basal activity. This might be due to the fact that peptides are usually not released under basal conditions, but are called into play upon activation of the system, when neuronal activity is increased. As reported for co-existing peptides and catecholamines in the CNS and the periphery, the classical neurotransmitter is released at low frequencies of electrical or chemical stimulation, whereas at higher frequencies or during bursting firing the peptide is released together with the classical neurotransmitter63^,64. Accordingly, neuropeptides may play a role in pathological states, when the system is up-regulated, such as during severe stress or injury, rather than under basal conditions⁶⁵. Therefore, antagonists acting on neuropeptide receptors may become important therapeutic agents, since they may act preferentially on pathologically activated systems. Although the first results obtained in humans have yet to confirm the therapeutic potential of most nonpeptide antagonists of peptide receptors, present available evidence based on animal studies indicates that these agents should be considered as highly promising for the development of new drugs.

97–139: 27-O-3-(2-[3-carboxyacryloylamino]-5-hydroxyphenyl)-acryloyloxymyricerone

A127722: trans-trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-([N,N-dibutylamino]carbonylmethyl)pyrrolidine-3-carboxylate

A81282: 4-(N-butyl-N-[{2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]amino)pyrimidine-5-carboxylic acid

A81988: 2-(N-n-propyl-N-[{2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]amino)pyridine-3-carbolic acid

antalarmin: N-butyl-N-ethyl-(2,5,6-trimethyl)-7-[2,4,6-trimethylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine

BIBP3226: R-N²-(diphenylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide

BIBS222: 2-n-butyl-1-(4-[6-carboxy-2,5-di-chlorbenzoylamino]-benzyl)-6-N-(methylaminocarbonyl)-n-pentylamino-benzimidazole

BIBS39: 4′-([2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl]-methyl)biphenyl-carboxylic acid

BMS180560: 2-butyl-1-chloro-1-([1-{2-(2H-tetrazol-5-yl)phenyl}-1H-indol-4-y]methyl)-1H-imidazole-5-carboxylic acid

BMS182874: 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulphonamide

BNTX: (5α)-17-(cyclopropylmethyl)-4,5-epoxy-3, 14-dihydroxy-7-(phenylmethylene)-morphinan-6-one hydrochloride

CAM4515: (S)-[1-(1H-indol-3-ylmethyl)-2-[methyl(phenylmethyl)amino]-2-oxoethyl]-2-benzofuranylmethyl ester, carbamic acid

CAM4750: [S-(R*,S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl[1-(4-pyridinyl)ethyl]amino]-2-oxoethyl]-2-benzofuranylmethyl ester monohydrochloride, carbamic acid

CGP49823: [(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl]-4-piperineamine] dihydrocloride

CP122721: (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine

CP154526: butyl-ethyl-(2,5-dimethyl-7-[2,4,6-trimethylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino

CP96345: [(2S,3S)-cis-2-(diphenylmethyl)-N-(2-iodophenyl)-methyl]-1-azabicyclo-[2.2.2]octan-3-amino

CP99994: (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine

CS866: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)methylimidazol-5-carboxylate

DMP811 (L708404): 4-ethyl-2-n-propyl-1-([2′-{1H-tetrazole-5-yl}biphenyl-4-yl]methyl)imidazole-5-carboxylic acid

DuP532: 2-propyl-4-pentafluorethyl-1-(2′-[2H-tetrazol-5-yl]-1,1′-biphenyl-4-yl-methyl)1H-imidazole-5-carboxylic acid

E4177: 4′-(2-cyclopropyl-7-methyl-3H-imidazo[5,4-b]pyridine-3-yl)methyl-2-biphenylcarboxylic acid

EXP3174: n-butyl-4-chloro-1-([2′-{1H-tetrazol-5yl}biphenyl-4-yl]methyl)imidazole-5-carboxylate

EXP3312: 2-n-propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde

EXP3892: 2-n-propyl-4-trifluoromethyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxilic acid

FK480: (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine-3-yl]-1H-indole-2-carboxamide

FR173657: (E)-3-(6-acetamido-3-pyridyl)-N-(N-[2,4-dichloro-3{(2-methyl-8-quinolinyl)oxymethyl}phenyl]-N-methylaminocarbonyl-methyl)acrylamide

FR193108: (+)-3-[[5-(2-fluorophenyl)-9-methyl-2-oxo-3-[[[[3-(1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-2,3-dihydro-1H-1,4--benzodiazepin-1-yl]acetyl]-3-azabicyclo[3.2.2]nonane

GR117289: 1-([3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid

GR159897: 5-fluoryl-3-ylethyl(4-[phenylsulphinylmethyl])piperidine

GR203040: (+)-(2S,3S and 2R,2R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)amine

GR205171: (2S-cis)-N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methyl]-2-phenyl-3-piperidinamine

GV150013: (+)-N-(1-[1-adamantane-1-methyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-N′-phenylurea

ICID6888: 2-ethyl-5,6,7,8-tetrahydro-4-([2′-{1H-tetrazol-5-yl}biphenyl-4-yl]methoxy)quinoline

ICID8731: 2-ethyl-4-([2′-{1H-tetrazol-5-yl}biphenyl-4-yl]methoxy)quinoline

KSG504: (S)-arginium(R)-4-[-N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphtylsulfonyl)pentanoate monohydrate

kuwanonH: [1S-(1a,5a,6b)]-8-[6-[2,4-dihydroxy-3-(3-methylbut-2-enyl)benzoyl]-5-(2,4-dihydroxyphenyl)-3-methylcyclohex-2-en-1-yl]-2-(2,4-dihydroxyphenyl)-5,7-dihydroxy-3-(3-methylbut-2-enyl)-4H-1-benzopyran-4-one

L158809: 5,7-dimethyl-2-ethyl-3-(2-[1H-tetrazol-5-yl]biphenyl-4-yl)lmidazol[4,5-b]pyridine

L161638: N-[2-ethyl-3-,4-dihydro-4-oxo-3-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-6-quinazolinyl]-N-(phenylmethyl)-2-thiophenecarboxamide

L161664: 1-(N,N-diphenylaminocarbonyl)-4-(′N′,N′-di-n-pentylaminocarbonyl)piperazine-2-diethylaminopropylcarboxamide

L163017: 6-(benzoylamino)-7-methyl-2-propyl-3-([2′-{N-(3-methyl-1-butoxy)carbonylaminosulfonyl}(1,1′)-biphenyl-4-yl]methyl)-3H-imidazo(4,5-b)pyridine

L365031: 1-methyl-3-(4-bromobenzoyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one

L365260: 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N′-(3-methylphenyl)urea

L367773: (1S,2S)-2,3-dihydro-1′-(((7,7-dimethyl-2-((4-imidazolylacetyl)amino)bicyclo[2.2.1]hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4′-piperidine), hydrochloride

L368899: 1-([2-{2-amino-4-(methylsulphonyl)butyramido}-7,7-dimethylbicyclo[2.2.1]-heptan-1-yl]methylsulphonyl)-4-(2-methylphenyl)piperazine

L368935: N-(1,3-dihydro-1-(2-methyl)-propyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N-([3-{1H-tetrazol-5-yl}phenyl]urea)

L371257: 1-(1-[4-{(N-acetyl-4-piperidinyl)oxy}-2-methoxybenzoyl]piperidinin-4-yl)-4H-3,1-benzoxazin-2-1H-one

L733060: (2S,3S)-3-([3,5-bis(trifluoromethyl)phenyl]methyloxy)-2-phenyl piperidine

L740093: N-([3R]-5-[3-azabicyclo{3.2.2}nonan-3-yl]-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-N′-(3-methylphenyl)urea

L742694: 2-(S)K[3,5-bis(trifluoromethyl)benzyl]oxy)-3-(S)-phenyl-4-(5-{3-oxo-1,2,4-triazolo}methylmorpholine

L743345: 3S-N-(3-azabicyclo[3.2.2.]nonan-3-yl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide

L749329: N-(2-[4-carboxy-2-propylphenoxy]-2-[dioxolo(e)phenyl]-acetyl)-(4-[1-methyl-ethyl)phenylsulfonylamide

L751281: dipotassium 4-(2-[1,3-benzodioxol-5-yl]-3-[4-isopropylphenylsulphonamido]-3-oxo-prop-1-yl)-3-propylbenzoate

L754142: dipotassium (−)-4-(1-[1,3-benzodioxol-5-yl]-2-[4-isopropylphenylsulphonamido]-2-oxoethoxy)-3-propylbenzoate

LR-B/081: methyl-2-([4-butyl-2-methyl-6-oxo-5-{[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl}-1 (6H)-pyrimidinyl]methyl)-3-thiophenecarboxylate

LY191009: trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-(4-[trifluoromethyl]phenylpyrazolidine-1-carboxamide

LY202769: 2-[2-(5-chloro-1H-indol-3-yl)ethyl]-3-[3-(1-methylethoxy)phenyl]-4(3H)-quinazolinone

LY242040: trans-3-oxo-4,5-diphenyl-N-(4-[trifluoromethyl]phenylpyrazolidine-1-carboxamide

LY247348: 2-[2-(1H-indol-3-yl)ethyl]-3-[3-(1-methylethoxy)phenyl]-4(3H)-quinazolinone

LY262684: trans-N-(4-bromophenyl)-4,5-bis(2-chlorophenyl)-3-oxopyrazolidine-1-carboxamide

LY262691: trans-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-pyrazolidinecarboxamide

LY288513: (4S,5R)-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-pyrrazolidinecarboxamide

LY303870: (R)-1-(N-[2-methoxybenzyl]acetylamino)-3-(1H-indol-3-yl)-2-(N-[2-{4-piperidin-1-yl}piperidin-1-yl}acetyl]amino)propane

LY306740: (R)-1-(N-[2-methoxybenzyl]acetylamino)-3-(1H-indol-3-yl)-2-(N-[2-{4-cyclohexylpiperazin-1-yl}acetyl]amino)propane

MDL105212A: [(R)-1-(2-[3-{3,4-dichlorophenyl}-1-{3,4,5-trimethoxybenzoyl}-pyrrolidin-3-yl]-ethyl-4- phenylpiperidine-4-carboxamide, hydrochloride

MEN10930: (S)-N-[1-[[[2-[methyl(phenylmethyl)amino]-1-(2-naphthalenylmethyl)-2-oxoethyl]amJno]carbonyl]cyclohexyl]-1H-jndole-3-carboxamide

MK966 (L159282): N-(4^′-[{5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b)pyridin-3-yl}methyl][1,1^′-biphenyl]-2-yl)sulfonylbenzamide

NB127914: 2-methyl-4-(N-propyl-N-cyclopropanemethylamino)-5-chloro-6-(2_,4,6-tri-trichloroanilino)pyrimidine

NTB: naltriben methasulfonate

OPC21268: 1-(1-[4-{3-acetylaminopropoxy}benzoyl]-4-piperidil)-3,4-dihydro-2-1H-quinolinone

OPC31260: 5-dimethylamino-1-(4-[2-methylbenzoylamino]benzoyl)-2,3,4_,5-tetrahydro-1H-benzazepine

PD123177: 1-(4-amino-3-methylphenyl)methyl-3-(diphenylacetyl)-4,5_,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylate

PD123319: (S)-1-(4-[dymethylamino]-3-methylphenyl)methyl-5-(diphenylacetyl)-4_,5,67-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylate

PD134308 (CI988): 4-([2-{(3-[1H-indol-3-yl]-2-methyl-1 oxo-2-[{(tricyclo[3.3.1.13^,7]dec-2-yloxy)carbonyl}amino]propyl)amino}-1-phenylethyl]amino)-4-oxo-(R-[R*R*])-butanoate-N-methyl-D-glucamine

PD135158: 4-([2-{(3-[1H-indol-3-yl]-2-methyl-1-oxo-2-[{(1.7.7-trimethyl-(bicyclo[2.2.1]hept-2-yl)oxy)carbonyl}amino]propyl)amino}-1-phenylethyl]amino)-4-oxo-[1S-1α.2β[S*(S*)]4α])-butanoate-N-(α-methyl-N-[{D-glucamine (bicyclo system 1S-endo)

PD140548: N-(α-methyl-N-[{tricyclo(3.3.1.1^3,7)dec-2-yloxy}carbonyl]-L-tryptophyl)-D-3-(phenylmethyl)-β-alanine

PD142898: benzenebutanic acid, β-([3-{1H-indol-3-yl}-2-methyl-2-[{[(2-methylcyclohexyl)oxy]carbonyl}amino]-1-oxopropyl]amino)-(1S-[1α{S*(R*)}-2β])

PD154075: [R-(R*S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2- benzofuranylmethyl ester, carbamic acid

PD154804: 3-(1,3-benzodioxol-5-yl)-4-cyclohexylmethyl-5-hydroxy-5-(4-methoxyphenyl)-2,5-dihydrofuran-2-one

PD155080: 2-benzo(1,3)dioxol-5-yl-3-benzyl-4-(4-methoxyphenyl)-4-oxobut-2-enoate

PD156707: 2-benzo(1,3)dioxol-5-yl-4-(4-methoxyphenyl)-4-oxo-3-(3,4_,5-trimethoxybenzyl)-but-2-enoate

PD159020: 3-(1,3-benzodioxol-5-yl)-1-(1,3-benzodioxol-5-ylmethyl)-5-methoxy-6-(phenylmethoxy)-1H-indole-2-carboxylic acid

PD159110: 3-(1,3-benzodioxol-5-yl)-1-(1,3-benzodioxol-5-ylmethyl)-6-propoxy-1H-indole-2-carboxylic acid

PD159433: 1-(1,3-benzodioxol-5-ylmethyl)-5,6-S-dimethoxy-3-[3,4,5- trimethoxyphenyl)thio]-lH--indole-2-carboxylic acid

PD161182: [S-(R*,S*)]-[2-(2,3-difluropheyl)-1-{(7-ureidoheptyl)carbamoyl}ethyl}carbamic acid-2-methyl-1-phenylpropyl ester

PD165929: (S)-α-[[[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]amino]-α-methyl-N-[[1-(2-pyridinyl)cyclohexyl]methyl]-1H-indole-3-propanamide

Ro462005: 4-tert-butyl-N-(6-[2-hydroxyetoxy]-5-[3-methoxyphenoxy]-4-pyrimidinyl)-benzenesulphonamide

Ro468443: (R)-4-tert-butyl-N-(6-[2,3-dihydroxypropoxy]-5-[2-methoxyphenoxy]-2-[4-methoxyphenyl]-pyrimidin-4-yl)-benzenesulphonamide

RP67580: (1–imino-2-[2-methoxyphenyl]ethyl)-7,7-diphenyl-4-perhydroisoindolone (3αR,7αR)

RP69758: 3-(3-[N-{N-methyl-N-phenyl-carbamoylmethyl}-N-phenyl-carbamoylmethyl]ureido)phenylacetic acid

RP71483: (E)-2-(3-[3-hydroxyiminomethyl-phenyl]ureido)-N-(8-quinolyl)-N-([1,2,3,4-tetrahydro-1-quinolyl]carbonylmethyl)acetamide

RP72540: (RS)-2-(3-[3-{N-(3-methoxyphenyl)-N-(N-methyl-N-phenyl-carbamoylmethyl)carbamoylmethyl}ureido]phenyl)propionic acid

RP73870: (RS)-([{N-(3-methoxyphenyl)-N-(N-methyl-N-phenyl-carbamoylmethyl)carbamoylmethyl}-3- ureido]-3-phenyl)-2-ethylsulfonate, potassium salt

RPR100893: (3nS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol

SB209598: 3-(2-carboxymethoxy-4-methoxyphenyl)-1-(6-chloro-1,3-benzodioxol-5-ylmethyl)-indole-2-carboxilic acid

SB209670: (+)-1S,2R,S-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxyindane-2-carboxylic acid

SB217242: 1S,2R,3S-3-(2-hydroxyethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylic acid

SB223412: (S)-(-)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide

SC51316: 5-([3,5-dibutyl-1H-1,2,4-trizol-1-yl]methyl)-2-(2-[1H-tetrazol-5-ylphenyl])pyridine

SC51895: 1,4-dibutyl-1,3-dihydro-3-([2^′-{1H-tetrazol-5-yl}[1,1^′-biphenyl]-4-yl]methyl)-2H-imidazol-2-one

SC52458: 2,5-dibutyl-2,4-dihydro-4-([2-{1H-tetrazol-5-yl}[1,1^′-biphenyl]-4^′-yl]methyl)-3H-1,2,4-triazol-3-one

SKF108566: (E)-α-([2-butyl-1 -{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]methylene)-2-thiophenepropanoate

SR 48692: 2-([1-{7-chloro-4-quinolinyl}-5-{2,6-dimethoxyphenyl}-1H-pyrazol-3-carbonyl]amino)adamantane-2-carboxylic acid

SR120107A: (R,R)-1-(2-[2-{2-naphtylsulphamoyl}-3-phenyl-propionamido]-3-[4-{N-(4-[dimethylaminomethyl]-cis-cyclohexylmethyl)amidino}phenyljpropionyl)-pyrrolidine

SR120819A: (R,R)-1-(2-[2-{2-naphtylsulphamoyl}-3-phenyl-propionamido]-3-[4-{N-(4-[dimethylaminomethyl]-trans-cyclohexylmethyl)amidino}phenyl]propionyl)-pyrrolidine

SR140333: (S)-1-(2-[3-{3,4-dichlorophenyl}-1-{3-isopropoxyphenylacetyl}piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo(2.2.2)octane chloride

SR142801: (S)-(N)-(1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phenylpiperidin-4-yl)-N-methylacetamide

SR142948A: 2-([5-{2,6-dimethoxyphenyl}-1-{4-(N-[3-dimethylaminopropyl]-N-methylcarbamoy-2-isopropylphenyl}-1H-pyrazol-3-carbonyl]amino)adamantane-2-carboxylic acid, hydrochloride

SR27897: 1-([2-{4-(2-chlorophenyl)thiazole-2-yl}aminocarbonyl]indolyl)acetic acid

SR48968: (S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylbenzamide

SR49059: (2S)-1 -([2R,3S]-[5-chloro-3-{chlorophenyl}-1-{3,4-dimethoxysulphonyl}-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide)

T0632: sodium (S)-3-(1-[2-fluorophenyl]-2,3-dihydro-3-[{3-isoquinolinyl}-carbonyl]amino-6-methoxy-2-oxo-1H-indole)propanoate

TBC11251: N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(6-methyl1,3-benzodioxol-5-yl)-1-oxoethyl]-thiopentene-3-sulphonamide

UP269-6: 5-methyl-7-propyl-8(-)[2^′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,4-triazolo]1,5-c]pyrimidin-2(3H)-one

UR7198: rel-(1R*,2R*)-3-[[4-(2-carboxy-1-phenylpropyl)phenyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazol[4,5-b]pyridine

UR7280:3-tert-butyl-1-propyl-5-([2′-{1H-tetrazol-5-yl}-1,1′-biphenyl-4-yl]methyl)-1H-pyrazole-4-carboxylic acid

WIN 64338: ([4-{(2-[{bis(cyclohexylamino)methylene}amino]-3-[2-naphthyl]-1-oxopropyl)amino}phenyl]methyl)tributylphosphonium chloride monohydrochloride

WIN51708:17β-hydroxy-17α-ethynyl-5α-androstanol[3,2-b]pyrimido[1,2-a]benzimidazole

WIN62577:[1R-(1α,3aβ,3bα,15aα,15bβ17aα)]-1ethynyl-2,3,3a,3b,4,5,15,15a,15b,16,17,17a-dodecahydro-15a, 17a-dimethyl-1H-benzimidazo[2,1-b]cyclopenta[5,6]naphto[1,2-g]quinazolin-1-ol

XR510:1-([2′-{[(isopentoxycarbonyl)amino]sulfonyl}-3-fluoro(1,1′-biphenyl)-4-yl]methyl)-5-(3-[N-pyridin-3-ylbutanamido]propanoyl)-4-ethyl-2-propyl-1H-imidazole, potassium salt

YF476: (3R)-N-(1-[tert-butylcarbonylmethyl]-2,3-dihydro-2-oxo-5-[2-pyridil]-1H-1,4-benzodiazepin-3-yl)-N′-(3-[methylamino]phenyl)urea

YM022: (R)-1-(2,3-dihydro-1-[2′-methylphenacyl]-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

YM087: 4′-(2-methyl-1,4,5,6-tetrahydroimidazo{4,5-d}{1}benzazepin-6-yl]carbonyl)-2-phenylbenzanilide monohydrocloride