Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization and Stille coupling - Switch of activity toward the serotoninand/or norepinephrine transporter

A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupl ing reaction. As hybrids between tropanes and quinuclidines, these tropaqui nuclidines represent a significant structural; departure from many of the o ther classes of tropane ligands synthesized to date. This structure class i s characterized by the boat conformation of the tropane ring and the orient ation of the additional bridge (and therefore of the nitrogen lone pair) to gether with the unusual placement of the aromatic moiety. All compounds wer e tested for their ability to inhibit monoamine reuptake under identical co nditions. The ability to inhibit reuptake of dopamine in comparison to: coc aine is generally decreased in this series but for one compound. (1S,3R,6S) -(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0(3.7)]-decane-2a beta-carbox ylic acid methyl ester (5h) exhibits reasonable activity at the dopamine tr ansporter (DAT) (K-i = 268 nM) and good activity at the norepinephrine tran sporter (NET) (K-i = 26 nM). The potency and selectivity shown by some of t hese ligands for the NET, serotonine transporter (SERT), or NET/SERT is str iking, particularly in view of the displacement of the aromatic ring in thi s series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R, 6S)-(Z)-9-(4-biphenylylmethylene)-7-azatricyclo[4.3.1.0(3.7)]-decane-2 beta -carboxyl acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K-i = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K-i = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,GS)-2-(acetoxymethyl)-(Z)-9-(3,4-dichlorophen ylmethylene)-7-azatricyclo[4.3.1.0(3.7)]decane]. This compound is a potent (K-i = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbr ain synaptosomes. Its Selectivity is about 400-fold over the NET and about 1000-fold over the DAT. The results of this study further demonstrate the p ossibility of tuning the selectivity of tropane analogues toward the SERT o r NET binding site. The ligands disclosed herein provide additional pharmac ological tools of use in attempting to correlate structure and transporter selectivity with in vivo studies of behavioral outcomes.