Original article Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole derivatives: Novel agonists for the CB 1 receptor Gerard P. Moloney a, * , James A. Angus b , Alan D. Robertson c , Martin J. Stoermer a , Michael Robinson a , Christine E. Wright b , Ken McRae a , Arthur Christopoulos d a Department of Medicinal Chemistry, Victorian College of Pharmacy (Monash University), 381 Royal Parade Parkville, Victoria, 3052, Australia b Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Victoria, 3010, Australia c AMRAD Corporation Limited (now known as Zenyth Therapeutics Limited) 576 Swan Street, Richmond, Victoria, 3121, Australia d Drug Discovery Laboratory, Department of Pharmacology, Monash University, Victoria, 3800, Australia Received 12 December 2006; received in revised form 6 April 2007; accepted 12 April 2007 Available online 6 May 2007 Abstract An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB 1 agonists. It is hoped that com- pounds 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 a series of 1-substituted-indole-3-oxadiazoles as potential CB 1 agonists. Crown Copyright Ó 2007 Published by Elsevier Masson SAS. All rights reserved. Keywords: Cannabinoid CB 1 receptors; CB 1 agonists; Pain control; Aminoalkylindoles; Design; Synthesis 1. Introduction There are two cannabinoid receptors designated neuronal (CB 1 ) and peripheral (CB 2 ) and both have recently been cloned [1,2]. Activation of both receptors leads to inhibition of adenylate cyclase and activation of mitogen-activated pro- tein 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 the management of glaucoma, motor dysfunction, appetite stimulation, emesis and, in particular, the treatment of chronic neuropathic pain [3e5]. In 1992, it was discovered that the en- dogenous 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 considerable and ongoing interest for the development of more tractable, organic small molecules that can achieve the same therapeutic effect without the difficulties associated with the use of peptides as therapeutic agents. Not surpris- ingly, a number of studies have already investigated analogues of anandamide as one means for achieving such a goal [8e13]. Molecular modeling studies have been performed on ananda- mide [14] and these and other studies have resulted in a pro- posed conformation of anandamide (1) for activity at the CB 1 receptor Chart 1 [15,16]. In recent times it has been demonstrated that the activity of a series of aminoalkylindole (AAI) antinociceptive agents, originally designed as non-ulcerogenic, non-steroidal antiin- flammatory drugs (NSAIDS) is associated with a second mechanism of action manifested by potent activity at * Corresponding author. Tel.: þ613 99039623; fax: þ613 99039651. E-mail address: gerard.moloney@vcp.monash.edu.au (G.P. Moloney). 0223-5234/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2007.04.007 Available online at www.sciencedirect.com European Journal of Medicinal Chemistry 43 (2008) 513e539 http://www.elsevier.com/locate/ejmech