PRECLINICAL PHARMACOLOGICAL ACTIONS OF (+ YDRO-5',6'-METHYLENE-DIOXY-1'-NAPHTHALENYL)METHYL] PYRROLIDINE METHANESULFONATE (ABT-200), A POTENTIAL ANTIDEPRESSANT AGENT THAT ANTAGONIZES ALPHA-2-ADRENERGIC RECEPTORS AND INHIBITS THE NEURONAL UPTAKE OF NOREPINEPHRINE/

-tetrahydro-5',6'-methylene-dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) was evaluated in a number of biological te sts to establish its pharmacological profile of activity. ABT-200 anta gonized the uptake of [H-3]-norepinephrine into synaptosomes of rat hy pothalamus (IC50 = 841 nM) and blocked 4,alpha-dimethyl-m-tyramine-ind uced hypermotility in rats. in addition, ABT-200 potently inhibited bi nding of [H-3]-rauwolscine to alpha-2 adrenergic receptors with a K-i value in radioligand binding assays of approximately 1 nM in the rat c ortex and was much less potent at other receptor binding sites. ABT-20 0 antagonized alpha-2 receptors in vitro in the rat vas deferens and d og saphenous vein, where pA(2) values of 7.7 and 8.2, respectively, we re obtained. ABT-200 also antagonized clonidine-induced mydriasis and increased the overflow of [H-3]-norepinephrine in guinea pig hippocamp al slices, manifestations of blockade of alpha-2 adrenoceptors in the central nervous system. ABT-200 was active in antagonizing nocturnal h yperactivity in olfactory bulbectomized rats, a test for putative anti depressant activity. In cardiovascular studies, ABT-200 exhibited negl igible activity in affecting hemodynamic parameters and was free of po stural hypotensive activity, In both in vitro and in vivo tests, ABT-2 00 was devoid of antihistaminic or anticholinergic activity. This prof ile of activity of moderate inhibition of norepinephrine uptake with b lockade of alpha-2 adrenoceptors suggests potential dual-action effect s for ABT-200, which may represent a putative antidepressant with mini mal cardiovascular side-effect liability.