ANTAGONISM OF 1-(2,5-DIMETHOXY-4-METHYLPHENYL)-2-AMINOPROPANE STIMULUS WITH A NEWLY IDENTIFIED 5-HT(2-) VERSUS 5-HT(1C)-SELECTIVE ANTAGONIST

DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5-HT1 C/2 serotonin agonist that exerts stimulus control of behavior in anim als. In order to determine if the discriminative stimulus effect of DO M is 5-HT1C- or 5-HT2-mediated, it would be informative to conduct tes ts of stimulus antagonism with a 5-HT1C- or 5-HT2-selective antagonist . To date, no such agents exist. Although the neuroleptic agent spiper one binds at D2 dopamine receptors and 5-HT1A serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT1C sit es and (b) it has been used as a ''5-HT2-selective'' antagonist. Becau se spiperone is a behaviorally disruptive agent, it is not suitable fo r use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure-affinity investigation was condu cted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lac k the disruptive actions of spiperone. Various modifications of the sp iperone molecule were examined, but most resulted in decreased 5-HT2 a ffinity or in loss of selectivity. One compound, l]-1-phenyl-1,3,8-tri azaspiro[4.5]decan-4-one(26), was shown to bind at 5-HT2 sites with hi gh affinity (K(i) = 2 nM) and >2,000-fold selectivity versus 5-HT1C si tes. In tests of stimulus antagonism using rats trained to discriminat e 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonis t (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated wi th spiperone. As such, (a) it would appear that the DOM stimulus is pr imarily a 5-HT2-mediated, and not 5-HT1C-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigation s where spiperone may not be a suitable antagonist.