A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK2) receptor antagonist 5 (JB93182), based on features shared with two ...related series. The technique uses “field points” as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK1. In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for ...recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of 125I-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- 1,2,4oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded ...derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
A series of 1,3,4-benzotriazepine-based CCK2 antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of ...1,4-benzodiazepine-based CCK2 antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK2 receptors to the earlier molecules and are highly selective over CCK1 receptors.
Novel, potent, and selective non-imidazole histamine H3 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 H3 receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H1 and H2, receptor subtypes and a 100-fold selectivity in the σ1 binding assay. Compounds 30 and 31 are the most potent, selective non-imidazole histamine H3 receptor antagonists reported in the literature to date.
A novel series of nonpeptide CCK2 receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzoh1,4diazonine (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-pyrido3,4-bindole 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 CCK2 receptor antagonist 5-(1S)-(3,5-dicarboxyphenyl)aminocarbonyl-2-phenylethylaminocarbonyl-6-(1-adamantylmethyl)aminocarbonylindole (JB93182 (3)). By this approach compounds such as (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-5-carboxymethylaminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzoh1,4diazonine (32) were prepared. Compound 32 behaved as a competitive CCK2 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 125ICCK-8S from CCK2 sites in mouse cortical homogenates (pK i = 6.99 ± 0.05). Compound 32 was 100-fold selective for CCK2 over CCK1 receptors based on the affinity estimate obtained in a guinea pig pancreas radioligand binding assay (pK i = 5.0).
Nonpeptide Cholecystokinin-2 Receptor Agonists Kalindjian, S. Barret; Dunstone, David J; Low, Caroline M. R ...
Journal of medicinal chemistry,
04/2001, Letnik:
44, Številka:
8
Journal Article
Recenzirano
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.
Elevated seawater CO2 can cause a range of behavioural impairments in marine fishes. However, most studies to date have been conducted on small benthic species and very little is known about how ...higher oceanic CO2 levels could affect the behaviour of large pelagic species. Here, we tested the effects of elevated CO2, and where possible the interacting effects of high temperature, on a range of ecologically important behaviours (anxiety, routine activity, behavioural lateralization and visual acuity) in juvenile yellowtail kingfish, Seriola lalandi. Kingfish were reared from the egg stage to 25 days post-hatch in a full factorial design of ambient and elevated CO2 (~500 and ~1000 μatm pCO2) and temperature (21 °C and 25 °C). The effects of elevated CO2 were trait-specific with anxiety the only behaviour significantly affected. Juvenile S. lalandi reared at elevated CO2 spent more time in the dark zone during a standard black-white test, which is indicative of increased anxiety. Exposure to high temperature had no significant effect on any of the behaviours tested. Overall, our results suggest that juvenile S. lalandi are largely behaviourally tolerant to future ocean acidification and warming. Given the ecological and economic importance of large pelagic fish species more studies investigating the effect of future climate change are urgently needed.
•The effects of elevated CO2 on behaviours of kingfish were trait specific.•Elevated CO2 increased anxiety in kingfish.•Exposure to high temperature in isolation had no significant effect on any behaviour.
The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly29-Trp30-Met31-Asp32-Phe33-NH2. Nevertheless, this congruence has not precluded using this ...structure to develop selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 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 CCK1-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 π-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)ethylamide, was a potent and selective CCK1 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 CCK1 antagonist with a conformation of CCK30 - 33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 receptors recognize enatiomeric dispositions of the Trp30 indole, Asp32 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 CCK30 - 33 and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.
A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo2.2.2octane (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 μmol kg-1 or less.
