RESUMEN
In the course of structural explorations around a series of potent CCK2 receptor antagonists, it was noted that simple N-methylation of the indolic N-H in the parent molecule gave rise to behavior in vivo that was consistent with the compound acting as an agonist. Exploration in vitro confirmed this property, and it was shown that the agonist action could be blocked by the reference CCK2 receptor antagonist, L-365,260. Further examples of this type of modification were explored, and a common theme with regard to agonist behavior was uncovered. Some molecular modeling is also presented in an attempt to throw light on the nature of the ligand receptor interactions that may be giving rise to the differing properties of these, apparently, structurally similar molecules.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/síntesis química , Indoles/síntesis química , Receptores de Colecistoquinina/agonistas , Adamantano/química , Adamantano/farmacología , Animales , Benzodiazepinonas/farmacología , Unión Competitiva , Corteza Cerebral/metabolismo , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Ligandos , Ratones , Modelos Moleculares , Pentagastrina/farmacología , Compuestos de Fenilurea/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/metabolismo , Estereoisomerismo , Estómago/efectos de los fármacosRESUMEN
The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH(2). Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK(1) or CCK(2) receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK(1) tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK(1)-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-D-Asp-2-phenylethylamido)-L-Trp-2-(2-naphthyl)ethylami de, was a potent and selective CCK(1) antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK(1) antagonist with a conformation of CCK(30)(-)(33) that others have proposed to be responsible for its activity at the CCK(2) receptor. The results suggest that CCK(1) and CCK(2) receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK(30)(-)(33) and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.
Asunto(s)
Oligopéptidos/síntesis química , Péptidos/química , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Colecistoquinina/química , Vesícula Biliar/efectos de los fármacos , Vesícula Biliar/fisiología , Ácido Gástrico/metabolismo , Cobayas , Técnicas In Vitro , Ligandos , Ratones , Modelos Moleculares , Imitación Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Oligopéptidos/farmacología , Páncreas/metabolismo , Fragmentos de Péptidos/química , Peptoides , Ratas , EstereoisomerismoRESUMEN
A novel series of nonpeptide CCK(2) receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole derivatives (4), in which the configuration of the substituents was established stereoselectively via the Pictet-Spengler reaction. Further structural manipulation was guided by molecular modeling through comparison of fieldpoint-based structures of candidate compounds with a selected low-energy conformation of the representative CCK(2) receptor antagonist 5-[[[(1S)-[[(3, 5-dicarboxyphenyl)amino]carbonyl]-2-phenylethyl]amino]carbonyl]-6- [[( 1-adamantylmethyl)amino]carbonyl]indole (JB93182 (3)). By this approach compounds such as (3R, 5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-5-carboxymet hyl aminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (32) were prepared. Compound 32 behaved as a competitive CCK(2) receptor antagonist in vitro as judged by its inhibition of pentagastrin-stimulated acid secretion in an isolated, lumen-perfused, immature rat stomach assay (pK(B) = 6.74 +/- 0.27) and by its displacement of [(125)I]CCK-8S from CCK(2) sites in mouse cortical homogenates (pK(i) = 6.99 +/- 0.05). Compound 32 was 100-fold selective for CCK(2) over CCK(1) receptors based on the affinity estimate obtained in a guinea pig pancreas radioligand binding assay (pK(i) = 5.0).
Asunto(s)
Quinonas/síntesis química , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Unión Competitiva , Diseño de Fármacos , Ácido Gástrico/metabolismo , Cobayas , Técnicas In Vitro , Modelos Moleculares , Páncreas/metabolismo , Quinonas/química , Quinonas/farmacología , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Novel, potent, and selective non-imidazole histamine H(3) receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H(3) receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H(1) and H(2), receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30and 31 are the most potent, selective non-imidazole histamine H(3) receptor antagonists reported in the literature to date.
Asunto(s)
Dimaprit/análogos & derivados , Dimaprit/síntesis química , Guanidinas/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Pirrolidinas/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Dimaprit/química , Dimaprit/farmacología , Diseño de Fármacos , Guanidinas/química , Guanidinas/metabolismo , Guanidinas/farmacología , Cobayas , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Ligandos , Contracción Muscular/efectos de los fármacos , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H3/metabolismo , Receptores sigma/metabolismo , Relación Estructura-ActividadRESUMEN
4-Chlorophenylmethanesulfonamide and (4-chlorobenzyl)sulfamide derivatives of histamine homologues were prepared and found to be potent and selective histamine H3 receptor antagonists. High receptor affinity and low differences in the data from the bioassays were achieved with the imidazol-4-ylbutyl analogues.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Histamina/análogos & derivados , Naftalenos/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Sulfonamidas/síntesis química , Animales , Diseño de Fármacos , Cobayas , Antagonistas de los Receptores Histamínicos/farmacología , Íleon/efectos de los fármacos , Íleon/metabolismo , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Naftalenos/farmacología , Sulfonamidas/farmacologíaRESUMEN
Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.
Asunto(s)
Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/síntesis química , Imidazoles/síntesis química , Receptores Histamínicos H3/química , Sulfonamidas/síntesis química , Animales , Cobayas , Cinética , Modelos QuímicosRESUMEN
A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.
Asunto(s)
Compuestos Policíclicos/farmacología , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Perros , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Compuestos Policíclicos/química , Ratas , Receptor de Colecistoquinina B , Especificidad de la EspecieRESUMEN
Experimental one-dimensional intensity and phase images of thick (>200 nm) oxide lines on silicon are presented together with profiles predicted from the waveguide model. Experimental results were obtained with a purpose-built Linnik interference microscope that makes use of phase-shifting interferometry for interferogram analysis. Profiles have been obtained for both TE and TM polarizations for a wide range of focal positions and in both bright-field [type 1(a)] scanning and confocal modes of microscope operation. The results show extremely good agreement despite several simplifying assumptions incorporated into the theoretical model to reduce computing times.
RESUMEN
We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.
Asunto(s)
Compuestos Policíclicos/química , Receptores de Colecistoquinina/antagonistas & inhibidores , Animales , Corteza Cerebral/metabolismo , Ratones , Estructura Molecular , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/metabolismo , Relación Estructura-ActividadRESUMEN
A variety of isosteres of the DNA polymerase inhibitor aphidicolin were synthesized as potential antiherpes agents. Modeling studies indicated that the bicyclooctane C, D rings of aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of aphidicolin. Of the racemic isosteres synthesized only 13, the compound with the greatest structural similarity to aphidicolin, showed any significant antiviral activity in primary assays. An enantioselective synthesis of the compound was carried out and the 4aS isomer 36 was shown to account for the observed antiviral activity noted against herpes simplex virus 1 and human cytomegalovirus.