Rigid analogs of dopamine: synthesis and interaction of 6-exo- and 6-endo-(3',4'-dihydroxyphenyl)-2-azabicyclo[2.2.2]octanes with dopamine uptake sites and receptors

Abstract
Two isomeric 6-endo-[1] and 6-exo-(3'',4''-dihydroxyphenyl)-2-azabicyclo[2.2.2]octane [2] were synthesized as semirigid analogs of dopamine (DA) to evaluate the preferred conformation of DA at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0.1 .mu.M [3H]DA by a synaptosomal preparation of corpus striatum from the reserpine-pretreated rat, 2 had a weak inhibitory effect that was 3 times greater than that of 1 (IC50 [mean inhibitory concentration] = 32 vs. 110 .mu.M). Interactions with DA receptors were assessed with competition for binding of [3H]apomorphine (APO) and on the effect on DA-sensitive adenylate cyclase. Both were virtually inactive against the binding of 0.5 nM [3H]APO at a screening concentration of 100 .mu.M. The experimental compounds also exhibited only slight adenylate cyclase stimulation in rat striatal homogenates, with 1 appearing to be somemhat more active (at 50 or 400 .mu.M). The weak activities of 1 and 2 and their relatively small differences in activity in these test systems suggest that the DA analogs interact only weakly with the DA transport and receptor sites, possibly as a result of the steric interference caused by the bulky bicyclic ring.
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