Rigid analogues 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.

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