Synthesis and Pharmacological Examination of Benzofuran, Indan, and Tetralin
Analogues of 3,4-( Methy1enedioxy)amphetamine
Aaron P. Monte, Danuta Marona-Lewicka, Nicholas V.Cozzi, and David E. Nichols
J. Med. Chem.
1993,36,3700-3706
Abstract
Benzofuran,indanandtetrahydronaphthalene analogsof3,4-(methy1enedioxy)amphetamine(MDA) were prepared in order to examine the role of the dioxolering oxygenatoms of MDA ininteracting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB(IC),MMAI(3),and(S)-(+)-amphetamine and for the ability to inhibit the uptake of [3H]serotonin, [3H]dopamine, and [3Hlnorepinephrine into crude synaptosome preparations.
Behaviorally,thebenzofuran and indan analogs4-6 produced similar discriminative cues,whereas the tetralin derivative 7 did not fully substitute for the training drugs. The results in the invitro pharmacology studies indicate that selectivity for 5-HTversus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms. However,the non oxygenated is ostere 6 possessed high potency at all uptake sites examined. Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.