title: Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies.
abstract: A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D007094:Imides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D007094:Imides; D010879:Piperazines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D001058:Apomorphine