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 synth esized and tested for inhibitor potency in [H-3]WIN 35,428 (WIN) binding at the dopamine (DA) transporter and [H-3]DA uptake assays. To demonstrate tr ansporter selectivity for the compounds, inhibitor potency was also tested using [H-3]nisoxetine and [H-3]paroxetine binding assays for the norepineph rine (NE) and serotonin (5-HT) transporters, respectively. Synthesis was ac complished by bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine with 2-cyclohexenone to give a mixture of endo- and exo-t rans-6-amino-5-phenylbicyclo[2.2.2]-octan-2-ones. The separated ketones wer e reduced to the four diastereomeric alcohols which were converted to acety l and benzoyl esters. The ketones, alcohols, and acetyl esters generally ha ve low affinity for the three transporters and do not effectively inhibit t he uptake of [H-3] DA. In all cases, the benzoates show significantly great er inhibition of WIN binding compared to the corresponding ketones, alcohol s, 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 cocain e 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-H T 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) dist ance or to the deviation of the nitrogen from the plane defined by the benz oate ring.