Thiophene Derivatives: A New Series of Potent Norepinephrine and Serotonin Reuptake Inhibitors Ao Zhang, a Guochun Zhou, a Suo-Bao Rong, a Kenneth M. Johnson, b Mei Zhang b and Alan P. Kozikowski a, * a DrugDiscoveryProgram,DepartmentofNeurology,GeorgetownUniversityMedicalCenter, 3900ReservoirRoad,NW,Washington,DC20007-2197,USA b DepartmentofPharmacologyandToxicology,UniversityofTexasMedicalBranch,Galveston,TX77555-1031,USA Received 4 January 2002; accepted 4 February 2002 Abstract—A series of (1S,3S,6R,10S)-(Z)-9-(thienylmethylene- or substituted thienylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decanes was prepared and evaluated for the ability to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters. Compound 5b is a NET-selective inhibitor, 5c is a mixed NET- and SERT-selective inhibitor, while 11 is a SERT-selective inhibitor. # 2002 Elsevier Science Ltd. All rights reserved. The biological actions of cocaine are believed to be cen- tered around its interaction at the dopamine, serotonin, and norepinephrine transporters (DAT, SERT, and NET). 1 4 However, in contrast to the substantial body of research on dopamine in the nucleus accumbens, com- paratively little attention has been given to the role of serotonin and norepinephrine. 5 7 As part of a project in pursuit of possible medications for cocaine abuse, we have paid particular attention on the design of ligands with selectivity for the SERT or the NET. 8 10 In a series of conformationally constrained tricyclic tropane analo- gues, several novel, highly potent and selective serotonin reuptake inhibitors have been identified, 9,10 which can be used as starting points for further research. For example, (1S,3S,6R,10S)-(Z)-9-(4-iodophenylmethylene)-10- (benzoyloxymethyl)-7-azatricyclo[4.3.1.0 3,7 ]decane (1) displayed a K i of 0.1 nM for 5-HT reuptake inhibition, while the 3-chloro-4-iodophenyl analogue (2) exhibited an even higher inhibitory potency (K i =0.06 nM) at the SERT. It is of further note that (1S,3S,6R,10S)-(Z)-9-(2 -thienylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decane-10- carboxylic acid methyl ester (5a), in contrast to the phenyl analogues, is a NE selective reuptake inhibitor (K i =26 nM). Since there are rather few studies on NE- selective reuptake inhibitors, and the thienyl group is an interesting pharmacophoric function, we decided to further investigate the SAR of thienyl analogues with ligand 5a as the lead. Herein, we report the synthesis and biological activity of a series of (1S,3S,6R,10S)-(Z)- 9-(thienylmethylene- or substituted thienylmethylene)- 7-azatricyclo[4.3.1.0 3,7 ]decanes, some of which exhibit good activities at the SERT or at the NET. The general strategy for the synthesis of these com- pounds is based on the procedures we developed pre- viously to prepare the lead 5a. 9 Thus, compounds 5b and 5c were prepared by Stille coupling reaction from the tributylstannyl precursor 3 in moderate yields (Scheme 1). 11 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00103-8 Bioorganic & Medicinal Chemistry Letters 12 (2002) 993–995 Scheme 1. *Corresponding author. Tel.: +1-202-687-0686; fax: +1-202-687- 5065; e-mail: kozikowa@georgetown.edu