CSIRO PUBLISHING Full Paper Aust. J. Chem. 2008, 61, 484–499 www.publish.csiro.au/journals/ajc Synthesis and Cannabinoid Activity of a Variety of 2,3-Substituted 1-Benzo[b]thiophen Derivatives and 2,3-Substituted Benzofuran: Novel Agonists for the CB 1 Receptor Gerard P. Moloney, A,E James A. Angus, B Alan D. Robertson, C Martin J. Stoermer, A Michael Robinson, A Lucy Lay, B Christine E. Wright, B Ken McRae, A and Arthur Christopoulos D A Department of Medicinal Chemistry,Victorian College of Pharmacy (Monash University), 381 Royal Parade, ParkvilleVIC 3052, Australia. B CardiovascularTherapeutics Unit, Department of Pharmacology, University of Melbourne, VIC 3010, Australia. C AMRAD Corporation Limited (now known as Zenyth Therapeutics Limited), 576 Swan Street, Richmond VIC 3121, Australia. D Drug Discovery Laboratory, Department of Pharmacology, Monash University, VIC 3800, Australia. E Corresponding author. Email: gerard.moloney@vcp.monash.edu.au An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB 1 agonists. It is hoped that compounds of this type will have clinical utility in pain control and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of several classes of 1-benzo[b]thiophen and benzofuran derivatives as novel CB 1 agonists.We have discovered a novel series of compounds, which contain a 1-benzo[b]thiophen or a benzofuran group as the central aromatic group. Our investigation of this series of compounds has enhanced our understanding of the importance of binding sites within the CB 1 receptor for favourable CB 1 potency. Our understanding of these factors allowed us to modify the structure of a 1-benzothiophen derivative and improve its potency at the CB 1 receptor. Manuscript received: 29 November 2007. Final version: 31 May 2008. Introduction There are two cannabinoid receptors designated neuronal (CB 1 ) and peripheral (CB 2 ). [1,2] Activation of both receptors leads to inhibition of adenylate cyclase and activation of mitogen- activated protein kinases. Activation of CB 1 receptors also leads to the gating of a variety of ion channels, including the inhibition of N-type voltage-dependent calcium channels. As a conse- quence of these cellular effects, together with the distribution of the receptors in neuronal tissues, cannabinoid CB 1 agonists have been suggested to offer significant therapeutic potential in vari- ous conditions including chronic neuropathic pain. [3–5] In 1992, it was discovered that the endogenous ligand for the CB 1 receptor is anandamide. [6] Anandamide 1 and a range of other structurally unrelated cannabinoid agonists have been shown to block the N-type calcium channel. Given that blockade of these channels by certain conotoxin peptides has already demonstrated clinical potential for the treatment of neuropathic pain, [7] there is con- siderable interest for the development of anandamide analogues as one means for achieving a similar therapeutic outcome. [8–13] Molecular modelling studies on anandamide [14] have resulted N H O OH H N O HO 1 1 Scheme 1. in a proposed conformation for activity at the CB 1 receptor (Scheme 1). [15,16] In recent times, it has been demonstrated that the activ- ity of a series of aminoalkylindole (AAI) antinociceptive agents, originally designed as non-ulcerogenic, non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a second mechanism of action manifested by potent activity at inhibit- ing electrically induced contractions of mouse vas deferens (MVD). [12,17–20] Studies on WIN-55,212–2 2, Pravadoline 3, and related compounds have shown that compounds from this struc- turally unrelated indole-based series (relative to the non-classical © CSIRO 2008 10.1071/CH07412 0004-9425/08/070484