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Chapter category: Neuropharmacology

Chemistry and Structure Activity Relationships for Tetrahydrocannibinols and Endocannabinoids

Chapter authors:
R.K. Razdan

An overview is presented of the chemistry and the known structure activity relationships (SAR) for tetrahydrocannabinols (THCs), endocannabinoids and pyrazole based an tagonists. An attempt has been made to highlight and put in perspective the cannabinoid work carried out before and after the discovery of the receptors. In the cannabinoid synthesis emphasis is placed on practical procedures in current use in the preparation of various analogs. For SAR studies the emphasis is on the areas of greatest influence in the structure of THCs (C-1, C-3 and C-9 positions), endocannabinoids (the head group and the end pentyl chain) and the pyrazole based antagonists (1-, 3-, 4- and 5-positions). A summary of the current SAR in each of the above areas is presented. The main active constituent responsible for the pharmacological effects of the marijuana plant is (-)-D9-6a,10a-trans-tetrahydrocannabinol (THC), generally known as D9-THC. It is present in the resinous exudates of the female flowers of Cannabis Sativa (family Moraceae), and its various preparations are known as hashish, charas, ganja, bhang, marihuana etc, depending on their mode of preparation and the country of origin. D9-THC belongs to a class of compounds called Cannabinoids, a term used for the typical C21 group of compounds present in the plant and includes their analogs and transformation products.1-3 Mainly in the last decade, many advances have been made in the cannabinoid field.4-9 At least two types of cannabinoid receptors, CB1 and CB2, have been discovered in mammalian tissues. The former occurs both inside and outside the central nervous system (CNS) and the latter is found mainly in the periphery. Both CB1 and CB2 receptors are G-protein coupled and function by coupling to a second messenger system. The role of CB1 receptors appears to be the modulation or suppression of the neuronal release of a range of excitatory and inhibitory transmitters in the brain. The role of CB2 receptors in the periphery is not yet clear but is most likely involved in the modulation of the immune system. It is now known that D9-THC produces a myriad of pharmacological responses by binding to both CB1 and CB2 cannabinoid receptors. The characterization of CB1 and CB2 receptors led to a search for endogenous ligands for the cannabinoid system. The most important of these “endocannabinoids” are arachidonylethanolamide (AEA, anandamide)10 and arachidonylglycerol (2-Ara-Gl)11,12 which act as neuromodulators or neurotransmitters.13 The dibenzopyran or the monoterpenoid numbering systems (Fig. 1) are generally used for naming the cannabinoids. Based on the monoterpenoid numbering system, D9-THC is also known as D1-THC. Along with D9-THC, numerous other cannabinoids are present in the plant and the structures of some of the important ones are shown in Figure 1. Over the years, several structure activity relationships (SAR) studies14-16 have been carried out using the structure of D9-THC, the natural material, as the template. This has resulted in several very potent agonists e.g.,11-hydroxy-D9-THC-DMH (dimethylheptyl), HU-210, DMHP, SP-1, BRL-4664, CP-55,940, nabilone etc. In addition, several aminoalkylindoles (AAIs) like WIN-55,212-2 have been identified as agonists and several pyrazole derivatives such as SR-141716A and SR-144528 have been shown to be potent antagonists for CB1 and CB2 receptors respectively. The natural THCs and the synthetic analogs with a tricyclic dibenzopyran core are referred to as classical cannabinoids, whereas the synthetic analogs (e.g.,CP-55,940) which have an open pyran ring and were developed by the Pfizer group in the 1980s, are called non-classical cannabinoids17. The endogenous ligands AEA and 2-Ara-Gl belong to the family of eicosanoids which represent yet another template for agonists. Various cannabinoid structures are shown in Figure 2, which raises the intriguing question of how such diverse chemical structures recognize the same receptor.

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