DETERMINATION OF SELECTIVE AND NONSELECTIVE COMPOUNDS FOR THE 5-HT1A AND 5-HT1B RECEPTOR SUBTYPES IN RAT FRONTAL-CORTEX

Abstract

There are multiple subtypes of the 5-hydroxytryptamine1 (5-HT1) receptor. Previously, evidence indicated that multiple states of the 5-HT1 receptor are present when the binding of [3H]-5-HT is measured in the absence of guanine nucleotides. When 1 mM GTP was present in the [3H]-5-HT receptor binding assay, the high affinity state was eliminated. As the presence of multiple states of a receptor complicates the interpretation of the inhibition of [3H]-5-HT binding caused by serotonin agonists and antagonists, the ability of a series of these drugs to compete for 15 nM [3H]-5-HT binding in the presence of 1 mM GTP was examined in the rat frontal cortex. Eight agonists and 5 antagonists showed selectivity for the 2 subtypes of the 5-HT1 receptor, whereas 3 agonists and 4 antagonists showed the same affinity for these 2 receptors subtypes. Most of the compounds examined exhibited only a modest 10- to 30-fold degree of selectivity; however, 1-(m-trifluoromethylphenyl) piperazine and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole were .apprx. 65-fold selective and spiperone was over 100-fold selective for one of the receptor subtypes. The subtype specificity of the selective compounds was determined using either spiperone, a selective 5-HT1A compound, or 1-(m-trifluoromethylphenyl) piperazine, a selective 5-HT1B compound, to preferentially inhibit one of the receptors. Evidently, spiperone, pizotifen and the indole agonists 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine are selective for the 5-HT1A receptor, whereas 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole and the piperazine agonists 1-(m-trifluoromethylphenyl) piperazine, 1-(m-chlorophenyl) piperazine and quipazine are selective for the 5-HT1B receptor. No antagonists selective for the 5-HT1B subtype were identified. Selective indole agonists evidently show a higher affinity for the 5-HT1A receptor and piperazine agonists demonstrate selectivity for the 5-HT1B receptor. The data are consistent with there being only 2 subtypes of the 5-HT1 receptor in rat frontal cortex.