Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters

Abstract

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers.

The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes

“…It is possible that the lipophilicity inherent in the 3,4-dichlorophenyl motif influenced the mode of interaction of these molecules with their binding site on the DAT. We had observed a similar effect previously in our exploration of 3,4-dichlorophenyl substituted tropanes11,10 The replacement of the 8-aza functionality with the 8-thia functionality can lead to a reduction in DAT inhibitory potency. Thus the 2β-(3-methylisoxazol-5-yl)-3β-(4-chlorophenyl)-8-thiabicyclo[3.2.1]octane (IC 50 = 0.59 nM) reported by Carroll13 is about ten times more potent at DAT inhibition than the directly analogous 8-thia compound, 6c (IC 50 = 7.2 nM).…”

“…The class of bicyclo[3.2.1]octanes,10,11 of which cocaine (Figure 1) is a member, has offered a springboard for the discovery of DAT selective inhibitors. Since 1973 when Clarke et al 12.…”

“…We proposed that the topological properties of tropane-like ligands (bicyclo[3.2.1]octanes) that bind to monoamine uptake systems was more important than the presence, or absence, of specific functionality, and we reported that 8-oxabicyclo[3.2.1]octanes (8-oxatropanes)16 and 8-thiabicyclo[3.2.1]octanes (8-thiatropanes)11 also manifested substantial binding potency at the DAT as well as selectivity versus SERT inhibition. The biological liability of the C2-ester became apparent to us in our early design of potential SPECT imaging agents13,17 when we had speculated that rapid in vivo hydrolysis of the C2-ester may have been a contributing factor toward erratic imaging results.…”

“…The starting unsaturated C2-methyl esters 1 provided the isoxazoles 4 as described below. These esters 1 were then reduced with samarium iodide to obtain both the 3α-aryl ( 2 ) and 3β-aryl ( 3 ) configured compounds, as we have described previously 11. Separation of the 3α- 2 and the 3β- 2 was cumbersome and time consuming.…”

“…The coupling constant between H 3 and H 2 and H 4 respectively ( J 3,2 = 11.5 Hz, J 3,4α = 13 Hz) confirmed transdiaxial interactions that can only be achieved in a boat conformation. Furthermore, the double double doublet for H 4α ( J 3,4α, = 13 Hz, J 4α,4β = 13 Hz, J 4α,5 = 2 Hz) evident in these C2-isoxazoles had proved diagnostic among boat conformers in all tropane-like classes of [3.2.1]bicyclooctanes 16,19,20,11. The 3β-aryl chair-configured 6a had H 2 δ 3.66 (dd), H 3 δ 3.43, H 4α, δ 1.36 (ddd), and H 4β δ 2.50 (ddd).…”