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. 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, with pharmacological manipulations to vary the releasable pool of NE from primarily vesicular to primarily extravesicular. Data were compared to previously reported closely related [2.2.2] ring system analogues. As found for [2.2.2] gauche analogues, endo [2.2.1] analogues (4a,b) were consistently less active than exo (trans antiperiplanar) analogues (3a,b). However, removing one methylene unit from the exo [2.2.2] ethylene bridge resulted in pronounced pharmacological differences in exo [2.2.1] analogues: 3b was equipotent with methamphetamine in biochemical [3H]NE release from extravesicular sites but physiological effects were masked by nonspecific depression; 3a showed loss of sensitivity to NE pool compartmentation (possibly via monoamine oxidase inhibition). Since minor structural modifications caused significant pharmacological differences, care should be exercised when using such compounds as tools for conformational preference assessment if pharmacological evaluations rely on effector membrane physiological viability.