RESUMEN
This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.
Asunto(s)
Benzofuranos/química , Encéfalo/metabolismo , Carbamatos/química , Carbamatos/síntesis química , Indoles/síntesis química , Antagonistas del Receptor de Neuroquinina-1 , Animales , Benzofuranos/metabolismo , Benzofuranos/farmacología , Carbamatos/metabolismo , Carbamatos/farmacología , Cristalografía por Rayos X , Gerbillinae , Miembro Posterior , Humanos , Enlace de Hidrógeno , Indoles/química , Indoles/farmacología , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Modelos Moleculares , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad , Sustancia P/administración & dosificación , Sustancia P/farmacologíaRESUMEN
The design, synthesis and biological actions of a novel, non-peptide CCK1 receptor agonist (PD 170292) which exhibits a similar pharmacological profile to the CCK analogue JMV180 is reported. PD 170292 was designed based on a consideration of the structures of a peptide based CCK1 receptor selective agonist and a peptoid CCK2 receptor selective antagonist.
Asunto(s)
Adamantano/análogos & derivados , Citrulina/análogos & derivados , Receptores de Colecistoquinina/agonistas , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Animales , Citrulina/síntesis química , Citrulina/química , Citrulina/farmacología , Peptoides , RatasRESUMEN
We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.
Asunto(s)
Adamantano/análogos & derivados , Ansiolíticos/síntesis química , Receptores de Colecistoquinina/antagonistas & inhibidores , Tetragastrina/análogos & derivados , Triptófano/análogos & derivados , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacocinética , Animales , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Disponibilidad Biológica , Barrera Hematoencefálica , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Modelos Moleculares , Estructura Molecular , Peptoides , Ratas , Ratas Wistar , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/metabolismo , Triptófano/síntesis química , Triptófano/química , Triptófano/farmacocinéticaRESUMEN
In this paper we describe the development of a novel series of non-peptide, "balanced" neuromedin-B preferring (BB1)/gastrin-releasing peptide preferring (BB2) receptor ligands as exemplified by PD 176252. PD 176252, which exhibits nanomolar affinity for both the BB1 (Ki = 0.15 nM) and BB2 (Ki = 1.0 nM) receptors, has been demonstrated to be a competitive antagonist at these bombesin receptor subtypes.
Asunto(s)
Indoles/metabolismo , Receptores de Bombesina/antagonistas & inhibidores , Animales , Péptido Liberador de Gastrina/metabolismo , Humanos , Indoles/química , Cinética , Ligandos , Modelos Químicos , Neuroquinina B/análogos & derivados , Neuroquinina B/metabolismo , Ratas , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
Over the last decade the increasing availability of metabolically- stable non-peptide antagonists targeted at neuropeptide receptors has led directly to a more thorough understanding of the role of neuropeptides in mammalian physiology. By far the majority of these non-peptide neuropeptide receptor antagonists thus far disclosed have been developed from leads identified from broad screening of company compound files or natural product collections, and may thus bear little obvious structural resemblance to the endogenous peptide ligand. This review will focus on an alternative structure-based approach to non-peptide neuropeptide receptor ligand design, referred to as the 'peptoid' drug design strategy, in which an appreciation of the structure of the neuropeptide is the key to the success of this approach. The development and current clinical progress of peptoid cholecystokinin and tachykinin receptor ligands that have thus far resulted from this process will be highlighted and used to exemplify the importance of this novel approach.
RESUMEN
A study of structure-activity relationships of a series of 'dipeptoid' CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-alpha-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum pi near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.
Asunto(s)
Antagonistas de Hormonas/química , Indoles/química , Meglumina/análogos & derivados , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Antagonistas de Hormonas/farmacología , Indoles/farmacología , Meglumina/química , Meglumina/farmacología , Ratones , Ratas , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/metabolismo , Relación Estructura-ActividadRESUMEN
The successful design of peptoid CCK-B receptor antagonists using rational approaches suggested that it might be feasible to develop similar non-peptide small molecule agonists with potential therapeutic applications. We now report the characterization of such a compound with full agonist activity at CCK-A receptors on rat exocrine pancreatic acinar cells. The compound, PD149164, stimulated a similar maximal response to CCK8 from the exocrine pancreas in anaesthetized rats in vivo, and from isolated pancreatic acini in vitro it also generated intracellular Ca2+ oscillations similar to those evoked by CCK8. These effects were inhibited by the CCK-A antagonist L-364,718. Interestingly, the enantiomer of PD149164, PD151932, was a CCK-A antagonist and blocked PD149164 stimulated effects on the exocrine pancreas. The data indicate that it is possible to develop both agonist and antagonist activities in enantiomers of small non-peptide molecules.
Asunto(s)
Receptores de Colecistoquinina/agonistas , Adamantano/análogos & derivados , Adamantano/metabolismo , Amilasas/metabolismo , Animales , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Antagonistas de Hormonas/química , Antagonistas de Hormonas/metabolismo , Indoles/química , Indoles/metabolismo , Meglumina/análogos & derivados , Meglumina/química , Meglumina/metabolismo , Ratones , Páncreas/metabolismo , Peptoides , Fenetilaminas/metabolismo , Ratas , Receptor de Colecistoquinina A , Receptores de Colecistoquinina/metabolismoRESUMEN
The novel radioligand [3H]PD140376 was used to label receptors that bind cholecystokinin (CCK) and related peptides in membranes prepared from guinea-pig brain and gastric glands. Under control conditions, measurements of the apparent affinity of 11 agonist and 16 antagonist ligands in both tissues revealed a strong positive relationship between the affinity of a compound in either tissue (slope of the regression line = 0.89, r2 = 0.908). Agonists consistently showed higher affinity for sites in gastric glands compared to brain. If agonists were excluded from the analysis, the degree of correspondence between affinities measured in each tissue was almost perfect (slope = 0.93, r2 = 0.986). In the presence of the guanyl nucleotide 5'-guanylimidodiphosphate (GppNHp), agonist affinity in gastric glands, but not brain, was reduced such that there was a direct relationship between binding affinity in each tissue. These data are consistent with the notion that the receptor sites in brain and gastric glands, which recognise CCK and gastrin related compounds, are the same and of the CCK-B/gastrin subtype. The receptors in the two respective tissues, however, do appear to differ in the degree of post-receptor coupling. These findings may explain previously reported differences between gastrin and CCK-B receptors that were based upon binding studies using agonist ligands.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/metabolismo , Dipéptidos/metabolismo , Antagonistas de Hormonas/metabolismo , Receptores de Colecistoquinina/metabolismo , Animales , Corteza Cerebral/metabolismo , Mucosa Gástrica/metabolismo , Cobayas , Receptor de Colecistoquinina BRESUMEN
The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)alphaMePheNH(CH2)7NHCONH2 (41, PD157672). This modified dipeptide has a Ke of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the alphaMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)ca r bamoyl]ethyl]carbamic acid 2-methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor selective antagonist. Compound 60 blocks the senktide-evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with Ke of 0.9 nM.
Asunto(s)
Dipéptidos/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Cobayas , Humanos , Técnicas In Vitro , Datos de Secuencia Molecular , Peptoides , Receptores de Neuroquinina-3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Two classes of structurally different tachykinin neurokinin3 (NK3) antagonists were used to evaluate species difference in antagonist binding between human and rat NK3 receptors. In competition binding experiments with [125I-MePhe7]NKB as radioligand, PD 154740, PD 157672, SR 48968, and SR 142801 displayed lower Ki values for the human NK3 receptor (40 +/- 4, 12 +/- 1,350 +/- 50, and 0.40 +/- 0.05 nM, respectively) than for the rat NK3 receptor (2450 +/- 130, 288 +/- 25, > 10,000, and 11.0 +/- 0.5 nM, respectively). Data from in vitro functional assay showed similar species preference as observed with the competition binding assay. It was shown previously that substitution of only two amino acid residues in the rat receptor to their human counterparts could change the species selectivity of SR 48968, a weak NK3 antagonist. In the double-substituted rat mutant, all three antagonists (PD 154740, PD 157672, and SR 142801) displayed Ki values (76 +/- 8, 16 +/- 2, and 0.50 +/- 0.05 nM, respectively) very similar to the Ki values for the wild-type human NK3 receptor. Thus, in addition to their previously reported effects on SR 48968, these two amino acid residues are responsible for the species selectivity of these three additional NK3 antagonists. Because PD 154740 and PD 157672 are very different structurally from SR 48968 and SR 142801, our results indicate that the two identified residues may be involved in adopting a receptor conformation that favors the binding of NK3 antagonists that display species preference for the human NK3 receptor.
Asunto(s)
Receptores de Neuroquinina-3/antagonistas & inhibidores , Animales , Benzamidas/farmacología , Unión Competitiva , Células CHO/metabolismo , Células CHO/ultraestructura , Cricetinae , Dipéptidos/farmacología , Humanos , Fosfatos de Inositol/metabolismo , Radioisótopos de Yodo , Cinética , Mutación , Neuroquinina B/análogos & derivados , Neuroquinina B/metabolismo , Neuroquinina B/farmacología , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Neuroquinina-3/metabolismo , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
1. Electrophysiological recordings from rat ventromedial hypothalamus (VMH) in vitro have been used to compare the effects of novel chemical entities on CCKB receptor activation in the rat central nervous system. 2. Twenty compounds from three different chemical series were evaluated for their ability to reduce pentagastrin-induced increases in action potential firing rate. 3. All twenty compounds studies were found to be CCKB antagonists, with equilibrium constants spanning a concentration-range of several orders of magnitude. The rank order for their ability to block pentagastrin responses correlated well with values obtained for their relative affinities for the mouse cortex CCKB binding site. 4. It is concluded that the VMH preparation provides a good functional correlate to binding assays in the rodent central nervous system for a structurally diverse series of CCKB antagonists.
Asunto(s)
Receptores de Colecistoquinina/antagonistas & inhibidores , Núcleo Hipotalámico Ventromedial/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Técnicas In Vitro , Ligandos , Masculino , Ratones , Pentagastrina/antagonistas & inhibidores , Ratas , Ratas Wistar , Relación Estructura-Actividad , Núcleo Hipotalámico Ventromedial/efectos de los fármacosRESUMEN
The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Triptófano/análogos & derivados , Animales , Proteínas Sanguíneas/metabolismo , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Diseño de Fármacos , Cobayas , Humanos , Íleon/efectos de los fármacos , Técnicas In Vitro , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Triptófano/síntesis química , Triptófano/química , Triptófano/farmacología , Vejiga Urinaria/efectos de los fármacosRESUMEN
The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).
Asunto(s)
Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Sitios de Unión , Colon/efectos de los fármacos , Cricetinae , Diseño de Fármacos , Técnicas In Vitro , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Oligopéptidos/química , Peptoides , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacosRESUMEN
The specific binding characteristics of the novel cholecystokinin (CCK)B/gastrin receptor-selective peptoid antagonist radioligand [3H]PD 140376 were investigated using membrane homogenates prepared from guinea pig cerebral cerebral cortex and gastric fundic mucosa. [3H]PD 140376 (0.01-10 nM) bound to both cerebral cortex and gastric gland homogenates with comparable high affinity (Kd, 0.1-0.2 nM) and to an apparent single population of sites with Bmax values of 119 and 296 fmol/mg of protein, respectively. The level of specific binding, defined as that displaced by unlabeled CCK sulfated octapeptide, was routinely between 60 and 70% in the cortex and between 50 and 60% in the fundic mucosa. Pharmacological characterization of the [3H]PD 140376-labeled binding sites with a series of agonist and antagonist ligands selective for each of the CCK receptor subtypes demonstrated, in both preparations, an affinity profile consistent with that of the CCKB/gastrin receptor. However, Hill slopes for the competition curves for the unlabeled agonist ligands against specific [3H]PD 140376 binding were significantly less than unity, whereas those for the antagonist ligands, including unlabeled PD 140376, were close to unity. The affinity and Hill slope for PD 140376 and the related CCKB/gastrin antagonist CI-988 were unaffected by the presence of the nonhydrolyzable GTP analogue guanylyl-5'-imidodiphosphate. In contrast, guanylyl-5'-imidodiphosphate caused a characteristic decrease in affinity and an increase in the Hill slopes towards unity for the agonist ligands CCK sulfated octapeptide and pentagastrin. The binding characteristics of unlabeled PD 140376 were also unaffected by the presence of the monovalent cation sodium. In conclusion, the present study has demonstrated that [3H]PD 140376 is the most potent and selective antagonist radioligand yet described for the characterization of CCKB/gastrin receptors in the central and peripheral nervous systems.
Asunto(s)
Hidrocarburos Aromáticos con Puentes , Corteza Cerebral/metabolismo , Dipéptidos , Mucosa Gástrica/metabolismo , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Unión Competitiva , Hidrocarburos Aromáticos con Puentes/metabolismo , Dipéptidos/metabolismo , Gastrinas , Cobayas , Técnicas In Vitro , Radioisótopos de Yodo , Cinética , Masculino , Peptoides , Ensayo de Unión Radioligante , Receptores de Colecistoquinina/metabolismo , Sincalida/análogos & derivados , Succinimidas , TritioRESUMEN
This paper outlines the synthesis of selected acid mimics of the non-peptide CCK-B selective antagonist CI-988, 1. CCK-B and CCK-A binding affinities of these analogues are described and their CCK-B affinity and selectivity rationalized by consideration of the pK(a) values, charge distribution, and geometry of the respective acid mimics. Several of the compounds have CCK-B binding affinities similar to the parent carboxylic acid 1 (CCK-B, IC50 = 1.7 nM; pK(a) = 5.6) and span a pK(a) range of less than 1 (sulfonic acid 27) to greater than 9.5 (5-thio-1,2,4-triazole 24). Among the more active compounds synthesized are tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[2-[[2-[[(3-hydroxy-5-isoxazolyl)acetyl]-amino]-2- phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl+ ++]carbamate (15), tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[(1-oxo- 3-sulfopropyl)amino]-2-phenylethyl]amino]-ethyl]carbamate, monosodium salt (27), and tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1- methyl-2-oxo-2-[[2-[[(1H-1,2,4-triazol-5-ylsulfinyl)acetyl]a mino]-2-phenylethyl]amino]ethyl]carbamic acid (34) which have CCK-B binding affinities of IC50 = 2.6, 1.3, and 1.7 nM, CCK-A/-B ratios of 650, 780, and 550 and pK(a) values of 6.5, less than 1, and 7.0, respectively.
Asunto(s)
Colecistoquinina/análogos & derivados , Dipéptidos/farmacología , Indoles/farmacología , Meglumina/análogos & derivados , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Ácidos Carboxílicos/química , Colecistoquinina/farmacología , Dipéptidos/química , Diseño de Fármacos , Indoles/química , Masculino , Meglumina/química , Meglumina/farmacología , Ratones , RatasRESUMEN
This paper describes the synthesis and structure-activity relationships (SAR) leading to the first rational design of "dipeptoid" analogues of the neuropeptide cholecystokinin (CCK). Compounds [R-(R*,S*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]-amino]-4-oxo-2-butenoic acid, [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-oxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid, and [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid (29d) have CCK-B binding affinities of IC50 = 0.8, 0.7, and 1.7 nM with a CCK-A/CCK-B ratio of 550, 1100, and 2500, respectively. Compound 27 is well-absorbed and is equiactive by the subcutaneous (sc) and intravenous (iv) routes of administration in the Ghosh and Schild test in rats in inhibiting pentagastrin stimulated gastric acid secretion with ED50 = 0.07 (0.01-0.34) mumol/kg. Compound 29d is anxiolytic in mice in the black-white test box over the range 0.0001-30 mg/kg sc, comparable in activity to diazepam over the range 0.125-1 mg/kg ip), and also active in this test when dosed orally over a wide range from 0.0001 to 10 mg/kg.