title: mCPP but not TFMPP is an antagonist at cardiac 5HT3 receptors.
abstract: The prototypic arylpiperazines, meta-chlorophenylpiperazine (mCPP), meta-trifluoromethylphenylpiperazine (TFMPP) and quipazine are widely studied serotonergic ligands with nonselective effects at 5HT1 and 5HT2 receptor subtypes. The present study was designed to compare the affinities of these arylipiperazines at 5HT3 receptors, and to determine agonist or antagonist activity at 5HT3 receptors. Quipazine showed high affinity at brain 5HT3 receptors (IC50 = 4.4 nM) and was a potent agonist of the von Bezold-Jarisch reflex in anesthetized rats, a response mediated by cardiac 5HT3 receptors. In concentrations that activated 5HT3 receptors, quipazine also antagonized serotonin-induced bradycardia in anesthetized rats. Taken together, these data suggest that quipazine is an agonist/antagonist with high affinity at 5HT3 receptors in both brain and cardiac tissue. Although mCPP also showed relatively high affinity at brain 5HT3 receptors (IC50 = 61.4 nM), it did not activate the von Bezold-Jarisch reflex; instead, mCPP potently antagonized serotonin-induced bradycardia. Thus, mCPP acts as an antagonist at 5HT3 receptors in the periphery. Although both quipazine and mCPP possessed relatively high affinity at brain 5HT3 receptors, TFMPP did not bind appreciably to 5HT3 receptors in brain (IC50 = 2373 nM) and neither activated nor inhibited cardiac 5HT3 receptors. That TFMPP did not interact with 5HT3 receptors, whereas quipazine and mCPP did, is in marked contrast to the similar effects of all three arylpiperazines at other serotonin receptors. The selectivity of TFMPP for 5HT1 and 5HT2 receptors (i.e., its minimal affinity for 5HT3 receptors) suggests that this arylpiperazine may be a preferred ligand relative to mCPP when studying 5HT1 or 5HT2 receptor mediated responses.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: W
authors.initials: W
authors.lastname: Bloomquist
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011814:Quipazine / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D010879:Piperazines; D011985:Receptors, Serotonin; C018406:1-(3-trifluoromethylphenyl)piperazine; D011814:Quipazine; C015068:1-(3-chlorophenyl)piperazine