MOLECULAR-GEOMETRY OF INHIBITORS OF UPTAKE OF CATECHOLAMINES AND SEROTONIN IN SYNAPTOSOMAL PREPARATIONS OF RAT-BRAIN

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 199  (3) , 649-661
Abstract
Several compounds of relatively rigid molecular structure exerted strong blockade of monoamine uptake by synaptosomal preparations of rat corpus striatum (dopamine and serotonin) and hypothalamus (norepinephrine). These include CP-24,441 (IR,4S-N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine), EXP-561 (4-phenylbicyclo[2.2.2]octan-1-amine), nomifensine and nefopam. The well-defined molecular geometry of the potent inhibitor EXP-561 suggest that the relative separation and orientation of phenyl and amino N in EXP-561 is a fundamental structural/conformational requirement for uptake blocking activity for the large family of phenylbutylamine- and phenoxypropylamine-related inhibitors. The tubular configuration of EXP-561 may be the most appropriate for blocking serotonin uptake. The requisite conformation for blocking dopamine uptake appears to be defined by the combination resulting from superimposition of the CP-24,441 and nomifensine structures. The conformation defined by the combination resulting from superimposition of the CP-24,441 and desipramine structures is apparently optimal for blocking norepinephrine uptake. The conformational requirements for diphenylpropylamine-related uptake blockers may be defined by the rigid compound CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2-naphthylamine). The actual potency of any given inhibitor is probably modulated by additional structural and stereochemical factors.