Pronounced Pharmacological Differences Arising from Minor Structural Changes in Conformationally Defined Amphetamine Analogues. Comparative Evaluation of endo- and exo-2-Amino- and endo- and exo-2-(Methylamino)benzobicycloheptene and -benzobicyclooctene Analogues...

Article abstract of DOI:10.1021/jm00180a006

The conformationally defined analogues of amphetamine, exo- (3a) and endo-2-aminobenzobicyclo<2.2.1>heptene (4a), and methamphetamine, exo- (3b) and endo-2-(methylamino)benzobicyclo<2.2.1>heptene (4b), were synthesized and their stereochemical assignments confirmed by NMR analysis.Benzonorbornen-2-one (7) was converted to its oxime (8), followed by the reduction to 4a.Amine 4b was produced from 7 by reductive amination with methylamine and NaBH3CN.Amine 3a was obtained by reduction of azide 5, formed from benzonorbornadiene and mercuric azide.Formylation of 3a, followed by hydride reduction, gave amine 3b.These compounds were evaluated for their ability to inhibit the uptake of <3H>norepinephrine(<3H>NE) into chopped cerebral cortex and atrial tissue, to increase locomotor activity in mice, and to increase the beating rate of isolated rat atria.Pharmacological manipulations were performed to vary the releasable pool of NE from primarily vesicular to primarily extravesicular in nature.The data were compared to those previously reported for the closely related amphetamine analogues exo- (1a) and endo-2-aminobenzobicyclo<2.2.2>octene (2a) and methamphetamine analogues exo- (1b) and endo-2-(methylamino)benzobicyclo<2.2.2>octene (2b).As was found for the conformationally restricted gauche analogues 2a and 2b in the <2.2.2> ring system, the endo <2.2.1> analogues (4a,b) were consistently less active than the trans antiperiplanar (exo) analogues.However, in the exo analogues (3a,b) removal of one methylene unit from the ethylene bridge of the exo <2.2.2> ring system resulted in pronounced pharmacological differences.While 3b was equipotent with methamphetamine in releasing <3H>NE from extravesicular storage sites as measured by biochemical methods (tracer studies), release of extravesicular NE as measured by physiological methods (isolated atria, locomotor activity) was apparently masked by a nonspecific depressant effect induced by the compound.These complicating factors were not observed for the <2.2.2> analogue 1b.Also, while both 1a and 1b showed a sensitivity to compartmentation of the releasable pool of <3H>NE, 3a, showed a loss of sensitivity (possibly through monoamine oxidase inhibition).Since these pharmacological differences occurred upon relatively minor structural modifications, care should be exercised in utilizing such compounds as tools for assessing conformational preferences when the pharmacological evaluation employed rest upon physiological viability of effector membranes