N,N-Dialkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]- benzamides, potent, selective d opioid agonists John R. Carson, * Steven J. Coats, Ellen E. Codd, Scott L. Dax, Jung Lee, Rebecca P. Martinez, Lou Anne Neilson,   Philip M. Pitis and Sui-Po Zhang Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, Welsh and McKean Roads, PO 776, Spring House, PA 19477-0776, USA Received 19 May 2003; accepted 10 February 2004 Abstract—A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the d opioid receptor with excellent selectivity versus the l opioid receptor. They were full agonists at the d opioid receptor, as assessed by stimulation of GTPcS binding, and displayed antinociceptive activity. Ó 2004 Elsevier Ltd. All rights reserved. Thediscoveryofmultipleopioidsubtypesin1976 1 gave risetohopesthatnewpainrelievingmedicationslacking the side associated with morphine would be discovered. Studies with the potent, d selective, cyclic peptide DPDPE, that showed good antinociceptive activity withoutconcurrenteffectonGImotility,amplifiedthese hopes. 2 The discovery of the nonpeptide d agonists BW373U86 3 (1a),TAN-67 4 (2),andSNC80 5 (1b)raised enthusiasm even higher. N N NEt 2 O Y CH 3 H 3 C H N N H 3 C H OH 1a Y = HO, BW373U86 1b Y = CH 3 O, SNC80 2 TAN-67 Upon further investigation, however, the expectations surroundingthenonpeptide d agonistsasanalgesicshave fallen short. SNC80 showed antinociceptive activity in mice in the models predictive of efficacy in severe pain butonlybyparenteralroutesandonlyathighdoses. 6 In addition, both BW373U86 and SNC80 induced convul- sionsinmice. 7 Theseresultschallengedthepotentialof d opioidagonistsastherapeuticagents. Meanwhile, the search for new d agonists has contin- ued. 8;9 Thestructuresofnewnonpeptide d agonistshave generally fallen into two classes, the compounds related to TAN-67 from the GlaxoSmithKline group and the structuresrelatedtoSNC80suchas 3, 10;11 4, 12 and 5. 13;14 Compounds of types 4 and 5 have shown impressive potency and selectivity. The challenges facing the cre- ators of new structural classes of d agonists, however, have been to overcome issues regarding safety and effi- cacyencounteredwiththefirstgenerationofnonpeptide d agonists. With these objectives in mind, we prepared and evaluated a series of N,N-dialkyl-4-[(8-azabi- cyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, 6, which combine the structural features of 4 and 5. N N R 1 NR 2 R 3 O X N N R 1 NR 2 R 3 O N R 1 NR 2 R 3 O X X 3 4 5 *Corresponding author. Tel.: +1-215-628-5526; fax: +1-215-628-3297; e-mail: jcarson@prdus.jnj.com   Present address: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.02.051 Bioorganic & Medicinal Chemistry Letters 14 (2004) 2109–2112