A-RING ORTHO-DISUBSTITUTED APORPHINE DERIVATIVES AS POTENTIAL AGONISTS OR ANTAGONISTS AT SEROTONERGIC 5-HT1A RECEPTORS

(R)- And (S)-11-hydroxy-10-methylaporphine 1 and 2 are, respectively, a potent, highly specific serotonergic (5-HT1A) agonist and antagonist . In an ongoing structure-activity study, racemates of the positional isomers 8-hydroxy-9-methyl- and 8-methyl-9-hydroxyaporphine were prepa red by modifications of literature methods and were resolved. The meth yl ethers of the target compounds were also evaluated pharmacologicall y. All of the free phenolic derivatives [(+)- and (-)-8 and 10] were i nert in an assay for 5-HT1A receptor activity. All of the methyl ether s [(+)- and (-)-9 and 11] demonstrated quantitatively similar low pote ncy stimulant effect at 5-HT1A receptors. The agonist or antagonist ac tivity exhibited by 1 and 2 reflects the high degree of structural spe cificity required of aporphine derivatives for action at 5-HT1A recept ors.