Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

Bilateral injections of either neurotensin (NT; 0.3, 1 or 5 micrograms in 1 microliter artificial CSF) or haloperidol (HA; 2.5 or 5 micrograms in 1 microliter 0.3% tartaric acid) into nucleus accumbens of rats markedly diminished the forward locomotion and rearing induced by d-amphetamine (AM; 2 mg per kg, IP). Neither NT nor HA affected the insomnia or sniffing component of AM arousal. Isovolumetric intra-accumbens injections of artificial CSF or the endogenous decapeptide, luteinizing hormone-releasing hormone (LHRH; 3 micrograms), did not affect AM behaviours. Since intra-accumbens injections of NT (1 microgram) or HA (2.5 micrograms) neither altered forward locomotion or rearing observed in untreated rats placed in an open field nor a variety of reflex activities, the observed effects of NT and HA in AM-treated rats were probably not due to impaired motor function per se. In contrast, NT does not produce neuroleptic-like effects when injected into nucleus caudatus; HA (5 micrograms) blocked stereotyped sniffing, licking, biting and head bobbing observed after AM (5 mg per kg, IP), but NT (3 or 5 micrograms) did not. Since NT and dopamine are present in substantial quantities in the nucleus accumbens, NT may act in the nucleus accumbens to modulate dopaminergic function.

We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound 1 (GW 5823), which is the first reported binding selective CCK-A full agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound 1 designed to explore changes to the C3 and N1 pharmacophores and their effect on agonist activity and receptor selectivity. Agonist efficacy in this series was affected by stereoelectronic factors within the C3 moiety. Binding affinity for the CCK-A vs CCK-B receptor showed little dependence on the structure of the C3 moiety but was affected by the nature of the second substituent at C3. Structure-activity relationships at the N1-anilidoacetamide "trigger" moiety within the C3 indazole series were also investigated. Both agonist efficacy and binding affinity within this series were modulated by variation of substituents on the N1-anilidoacetamide moiety. Evaluation of several analogs in an vivo mouse gallbladder emptying assay revealed compound 1 to be the most potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.

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