Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents:  2-Substituted-6-amino-5-phenylbicyclo[2.2.2]octanes

A series of 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes was synthesized and tested for inhibitor potency in [3H]WIN 35,428 (WIN) binding at the dopamine (DA) transporter and [3H]DA uptake assays. To demonstrate transporter selectivity for the compounds, inhibitor potency was also tested using [3H]nisoxetine and [3H]paroxetine binding assays for the norepinephrine (NE) and serotonin (5-HT) transporters, respectively. Synthesis was accomplished by bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine with 2-cyclohexenone to give a mixture of endo- and exo-trans-6-amino-5-phenylbicyclo[2.2.2]octan-2-ones. The separated ketones were reduced to the four diastereomeric alcohols which were converted to acetyl and benzoyl esters. The ketones, alcohols, and acetyl esters generally have low affinity for the three transporters and do not effectively inhibit the uptake of [3H]DA. In all cases, the benzoates show significantly greater inhibition of WIN binding compared to the corresponding ketones, alcohols, or acetate esters. One compound, (1R/S,4R/S)-6R/S-(N,N-dimethylamino)-5R/S-phenylbicyclo[2.2.2]oct-2S/R-yl benzoate, is almost as potent as cocaine in binding to the DA transporter (IC50 = 270 nM versus 159 nM for cocaine). The C-2 epimer, (1R/S,4R/S)-6R/S-(N,N-dimethylamino)-5R/S-phenylbicyclo[2.2.2]oct-2R/S-yl benzoate, was selective and potent in binding to the 5-HT transporter (IC50 = 53 nM versus 1050 nM for cocaine) as compared to the DA transporter (IC50 = 358 nM). A preliminary molecular modeling study of the benzoyl esters indicates that their relative potencies in the WIN binding assay are not correlated to the nitrogen to benzoate phenyl (centroid) distance or to the deviation of the nitrogen from the plane defined by the benzoate ring.