Abstract

A series of phenyl substituted 1-aminotetraline (1-amino-1,2,3,4-tetrahydronapththalene) derivatives was examined for effects on uptake of exogenous ³H-norepinephrine into rat heart and on reserpine-induced hypothermia in mice. trans-4-Phenyl derivatives with small nitrogen substituents were found to block norepinephrine uptake and to reverse reserpine-induced hypothermia with consistently greater effectiveness than their often inactive cis isomers. 1R,4S-N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine (1aα) was the most potent uptake blocker of this series. Its enantiomer was inactive, indicating the existence of a stereospecific receptor at the norepinephrine uptake pump. The structural and functional resemblance of this compound to desipramine suggests that in the active conformation the aminoalkyl side chain of tricyclic antidepressants is folded toward the aromatic ring. This hypothesis is supported by the potent uptake blockade observed with the nontricyclic agent, EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane), and by the relative inactivity of cyproheptadine [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine].