Synthesis and pharmacology of site specific cocaine abuse treatment agents: 8-substituted isotropane (3-azabicyclo[3.2.1]octane) dopamine uptake inhibitors

Abstract

A series of 8-substituted-3-azabicyclo[3.2.1] octanes (isotropanes) were synthesized and tested for inhibitor potency using [3H]WIN 35,428 binding at the dopamine (DA) transporter, [3H]citalopram binding at the serotonin (5-HT) transporter, and [3H]DA uptake assays. The synthesis started with a Mannich condensation of cyclopentanone, benzylamine, and fomaldehyde to afford N-benzyl-3-azabicyclo [3.2.1]octan-8-one (6). The 8-phenyl group was introduced by Grignard addition to ketone 6 or nucleophilic displacement via a triflate of the corresponding alcohol 7a. The 8β-phenyl-8α-alcohols from Grignard addition generally have low affinity for the two transporters and do not effectively inhibit the uptake of [3H]DA. The 8β-phenyl compound (14) without the hydroxyl group at C-8 was much more potent (22-fold) for [3H]WIN 35,428 binding inhibition than the corresponding 8β-phenyl-8α-hydroxy compound (7a). The 8α-phenyl compound 8a was almost as potent as cocaine in binding to the DA transporter (IC50 = 234 nM vs 159 nM for cocaine), whereas the C-8 epimer, compound 14, was somewhat less potent (IC50 = 785 nM). The lower potency of 14 (β-orientation of 8-phenyl group) as compared to 8a (α-orientation) was unexpected, based on modeling studies comparing the new compounds to WIN 35,065-2, an analogue of cocaine. The benzhydryl ethers at C-8 (17), analogous to the benztropines, had better selectivity than the corresponding phenyl compounds, 8a and 14, for the DA transporter as compared to the 5-HT transporter. The isotropane and benzisotropine analogues seem to bind in a manner that is more similar to that of the benztropine compounds 5 rather than those of cocaine and WIN 35,065-2.