M-CHLOROPHENYLPIPERAZINE AND M-TRIFLUOROMETHYLPHENYLPIPERAZINE ARE PARTIAL AGONISTS AT CLONED 5-HT2A RECEPTORS EXPRESSED IN FIBROBLASTS

Serotonin(2A) (5-HT2A) and 5-HT2C receptors share numerous pharmacolog ical properties. Two compounds thought to discriminate between these t wo receptor subtypes are m-chlorophenylpiperazine (mCPP) and m-trifluo romethylphenylpiperazine (TFMPP). These two drugs have been classified as antagonists at 5-HT2A receptors but as agonists at 5-HT2C receptor s on the basis of phosphoinositide hydrolysis studies in cerebral cort ex and choroid plexus, respectively. To determine more fully the prope rties of mCPP and TFMPP at 5-HT2A receptors, NIH 3T3 fibroblasts trans fected with the 5-HT2A receptor complementary DNA (GF6 cells) were use d as a model system of receptor function. These cells express approxim ately 15-fold higher 5-HT2A receptor density than is found in cerebral cortex. In GF6 cells, mCPP and TFMPP dose-dependently stimulated phos phoinositide hydrolysis with maximal effects less than that of 5-HT. T his agonist activity was blocked by 5-HT2A receptor antagonists but no t by prior treatment with pertussis toxin. Partial inactivation of 5-H T2A receptors with phenoxybenzamine decreased the maximal effects of m CPP and TFMPP but did not eliminate agonist activity. Thus mCPP and TF MPP are partial agonists at 5-HT2A receptors in GF6 cells, and these a gonist properties are retained even under conditions where receptor de nsity is comparable to that of cerebral cortex. Although it has not ye t been demonstrated that mCPP and TFMPP are agonists at central 5-HT2A receptors, this possibility should be considered when evaluating in v ivo effects of these drugs.