STRUCTURE-ACTIVITY-RELATIONSHIPS FOR COCAINE CONGENERS IN INHIBITING DOPAMINE UPTAKE INTO RAT-BRAIN SYNAPTIC VESICLES AND BOVINE CHROMAFFINGRANULE GHOSTS

Structure-activity relationships of cocaine congeners were determined in inhibiting reserpine-sensitive, Mg++/ATP-dependent uptake of [H-3]d opamine into rat brain synaptic vesicles under initial velocity condit ions. The C-2 carbomethoxy group could be deleted without loss of acti vity, whereas movement of this group from axial to equatorial orientat ion increased the potency. There was no need for the ester linkage bet ween the tropane and phenyl rings, nor was there need for the ethylene bridge between C-1 and C-5 that makes cocaine a tropane instead of a piperidine structure. The structure-activity relationships were differ ent from those for inhibiting neuronal amine transport or blocking vol tage-dependent sodium channels. There was no correlation between block of uptake and degree of lipophilicity. The equally lipophilic compoun ds cocaine and pseudococaine, and WIN 35,0653 and WIN 35,140, differed in uptake-blocking potency by an order of magnitude (137 vs. 22 mu M and 65 vs. 4 mu M, respectively). In bovine chromaffin granules, used as a less complex model system for the vesicular uptake system, the ra nk order of d-amphetamine, cocaine and pseudococaine in perturbing the proton gradient and in changing the membrane potential was different from that in inhibiting uptake. The inhibition of uptake is discussed in terms of the compounds acting as weak bases, transporter substrates or transporter blockers.