title: Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity.
abstract: The Ki values for etoperidone, trazodone and MCPP (m-chlorophenylpiperazine dihydrochloride) at 5-HT1A sites (using rat cerebral cortical synaptosomes and [3H]8-OH-DPAT) were determined to be 20.2, 23.6 and 18.9 nM, respectively. In an effort to elucidate the functional nature of the interaction at 5-HT1A sites in vivo, the ability of each compound to elicit reciprocal forepaw treading (RFT) or to block the RFT induced by 8-OH-DPAT in reserpinized rats was tested. Specifically, 8-OH-DPAT (1.0 mg/kg SC)-challenged or non-challenged (control) reserpinized (1.0 mg/kg SC) rats were administered etoperidone, trazodone or MCPP (IP) and scored for the elicitation of RFT (indicative of 5-HT1A agonistic activity) or for block of RFT induced by 8-OH-DPAT (indicative of 5-HT1A antagonistic activity). Reference compounds confirmed the specificity of the test. We report that etoperidone, trazodone and MCPP inhibited 8-OH-DPAT-induced RFT (ID50 = 17.4, 23.8 and 13.4 mg/kg, respectively). Only marginal RFT was produced in non-challenged animals by etoperidone and trazodone at a high dose (40 mg/kg). Taken together, the results suggest a predominant antagonistic activity of etoperidone, trazodone and MCPP at 5-HT1A receptor sites in rat central nervous system. However, one cannot rule out the possibility that these compounds are weak partial agonists. This activity may be relevant to the antidepressant action of these compounds.
authors.affiliation: Drug Discovery Research, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
authors.forename: R B
authors.initials: RB
authors.lastname: Raffa
authors.forename: R P
authors.initials: RP
authors.lastname: Shank
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012110:Reserpine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors; D014196:Trazodone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C013528:etoperidone; D014196:Trazodone