title: Synthesis and atypical antipsychotic profile of some 2-(2-piperidinoethyl)benzocycloalkanones as analogues of butyrophenone.
abstract: Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D1 receptors (Ki's in the micromolar range: 1.09-2.81) were slightly lower than that showed by haloperidol (Ki's in the nanomolar range: 5.01 and 97.72 for D2 and for D1 receptors, respectively). The ratio of pKi's values D1/D2 showed that the new molecules are more D2-selective than haloperidol. In contrast, in the [3H]-ketanserin binding assays the new compounds had greater affinity for 5-HT2A receptors (pKi's 7.89-8.60) than haloperidol (pKi 7.70) and in functional studies, endothelium-stripped aorta rings, the pA2 values (6.75-8.12) were slightly lower than that of ketanserin (8.87) in suppressing serotonin-induced contractions. The pKi's for D2 binding (and to a lesser extent pKi's for D1 binding) tend to be greater among typical (classical) than among atypical antipsychotics, while these two classes of antipsychotics exhibit no difference with regard to pKi's for 5-HT2A receptors. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds, and its potential induction of extrapyramidal symptoms (ratio values > 1.12 were predictive of an atypical antipsychotic profile). The new molecules had a ratio value in the range 1.08-1.20, while haloperidol showed a ratio of 0.93. In the behavioral screening tests, the new molecules showed antagonist activity of amphetamine-inducing hyperactivity and apomorphine-induced climbing (predictive tests for antipsychotic activity). In the catalepsy test (predictive test for induction of extrapyramidal symptoms), the values obtained were in accordance with an atypical antipsychotic drugs profile.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Fontenla
authors.forename: J
authors.initials: J
authors.lastname: Osuna
authors.forename: E
authors.initials: E
authors.lastname: Rosa
authors.forename: M E
authors.initials: ME
authors.lastname: Castro
authors.forename: T
authors.initials: T
authors.lastname: G-Ferreiro
authors.forename: I
authors.initials: I
authors.lastname: Loza-García
authors.forename: J M
authors.initials: JM
authors.lastname: Calleja
authors.forename: F
authors.initials: F
authors.lastname: Sanz
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez
authors.forename: E
authors.initials: E
authors.lastname: Raviña
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001058:Apomorphine / Q000494:pharmacology; D002090:Butyrophenones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D003342:Corpus Striatum / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005625:Frontal Lobe / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists
chemical_list: D014150:Antipsychotic Agents; D002090:Butyrophenones; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin; D000661:Amphetamine; D006220:Haloperidol; D001058:Apomorphine