From cannabis to cannabinergics: new therapeutic opportunities

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Abstract

The molecular basis of cannabinoid activity is better understood since the discovery of the CB1 receptor in the mammalian brain and the CB2 receptor in peripheral tissues. Subsequently, an endogenous CB1 receptor ligand, arachidonylethanolamide (anandamide), was isolated from porcine brain and shown to be metabolized by the enzyme arachidonylethanolamide amidohydrolase or fatty acid amide hydrolase. Recently, we have characterized a reuptake system for the transport of anandamide across the cell membrane, and have shown that selective inhibition of this transporter is associated with analgesia and peripheral vasodilation. The four cannabinoid system proteins, including the CB1 and CB2 receptors, fatty acid amide hydrolase, and the anandamide transporter, are excellent targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. During the last decade, numerous selective ligands for each of these proteins were designed and synthesized. Many of these agents serve as important molecular probes, providing structural information about their binding sites, as well as pharmacological tools imparting information about the roles of their targets in physiological and disease states. All of the above compounds that modulate the functions of the endocannabinoid system can be collectively described under the term cannabinergics, regardless of chemical classification or type of resultant pharmacological action.

Introduction

Today, cannabis or marijuana is the focus of strong social, legal, and medical controversy over its therapeutic utility. In 1997, two referenda in Arizona and California and, later, others in eight additional states, aimed at providing legal status to marijuana cigarettes for medical purposes. Two licensed single-compound cannabimimetic pharmaceuticals, Marinol® [Dronabinol, (−)-Δ9-tetrahydrocannabinol (Δ9-THC) from Roxane Laboratories (Columbus, OH, USA)] and Cesamet® [Nabilone developed at Eli Lilly (Indianapolis, IN, USA) now in use in the United Kingdom], are marketed for two indications: the control of nausea and emesis produced by cancer chemotherapy and as appetite stimulants in acquired immunodeficiency syndrome (AIDS)-related anorexia. Both of these agents have proven to be superior to conventional anti-emetics such as perchlorperazine in clinical trials with cancer chemotherapy patients (Breivogel & Childers, 1998).

Beyond this relatively limited medical use of cannabinoids and cannabimimetic agents, the ongoing, long-delayed elucidation of their pharmacology is likely to lead to a wide expansion of their clinical potential and significance. The understanding of cannabinoids and their biology was delayed for two main reasons (Mechoulam & Feigenbaum, 1995). The first was the gum-like, non-crystalline nature of the biologically active terpenoid ingredients of Cannabis sativa. (−)-Δ9-THC, the main active ingredient, was isolated and identified only in 1964 (Mechoulam & Gaoni, 1967). The second reason for this delay in progress was the long-standing scientific misconception that the cannabinoid-induced pharmacological actions are not mediated through specific receptors, but by perturbation of cellular membranes. This hypothesis deterred the pursuit of possible specific cannabinoid binding sites for many years. Due to their high lipophilicity, cannabinoids were paralleled with general anesthetics in terms of their mechanism of action (Paton, 1975). Although cannabinoids were found to clearly perturb membranes (Makriyannis et al., 1987), such effects were never shown to be solely responsible for their biological activity.

Section snippets

The CB1 receptor

In 1988, Devane et al. were the first to demonstrate the existence of specific cannabinoid binding sites in the rat brain. Definitive proof of the existence of the cannabinoid receptor came from Matsuda et al. in 1990 when they isolated the cDNA of a cannabinoid receptor from a rat cerebral cortex cDNA library and expressed it in CHO cells. This receptor was named CB1, and its 472 amino acid sequence revealed that it is a member of the G-protein-coupled receptors (GPCRs) Matsuda et al., 1990,

The endogenous ligands

The discovery of the cannabinoid receptors and their G-protein-coupled nature strongly suggested the existence of one or more endogenous cannabimimetic ligands that exert their physiological activity upon binding to these receptors. Initial efforts to identify a possible protein (Nye et al., 1988) or other water-soluble endogenous cannabimimetic ligands were unsuccessful (Deadwyler et al., 1995). The hypothesis that such a putative endocannabinoid should be lipophilic, like the classical

Endocannabinoid metabolism

During the past 5 years, there has been considerable progress in our understanding of the physiological pathways that are involved in the synthesis and inactivation of endocannabinoids. Anandamide is currently believed to be formed from membrane phospholipids through a pathway that involves (1) a transacylation of the amino group of phosphatidylethanolamine with arachidonate from the sn-1 position of phosphatidylcholine and (2) a D-type phosphodiesterase activity on the resulting

The endocannabinoid system

It is apparent from the above discussion that during the last 10 years, a series of important discoveries have unveiled a new, important biological assemblage, the endocannabinoid system. This system, which is evolutionarily well preserved, consists of at least two receptors, each with different localizations and functions; a family of endogenous ligands; and a specific molecular machinery for the synthesis, transport, and inactivation of these ligands. Although new information about this

Major classes of cannabinergic ligands

Based on chemical structure, cannabinergic ligands are classified into five major classes. The term cannabinergic encompasses ligands that act on proteins of the endocannabinoid system, regardless of chemical classification or type of resultant pharmacological activity. Therefore, this general term includes agents that act on the cannabinoid receptors, either as activators or antagonists, as well as molecules that inhibit the FAAH or AT. This is distinct from the term cannabimimetic, which

Therapeutic potential of cannabinergic agents

Most known cannabimimetics today have very broad effects on organ systems, some of which are still unexplained. The ubiquitous pharmacology of cannabimimetics is one of the reasons why the clinical application of these drugs has not yet reached its full potential. The following sections summarize the effects of cannabinergics on the various physiological systems and the possible therapeutic uses that may emanate from these effects.

Conclusions

Cannabinoid research has yielded much information and has taken us toward a better understanding of the molecular mechanisms of cannabinoid action, especially with the discovery of anandamide and 2-AG, two new families of endocannabinoids. Currently, there are multiple known endocannabinoid proteins (at least two receptors, CB1 and CB2; an enzyme, FAAH; and a transport protein, AT) as potential therapeutic targets for developing useful medications in the treatment of a multitude of ailments,

Acknowledgements

Research in the A. Makriyannis laboratory is funded by the National Institutes on Drug Abuse (Grants DA9158, DA03801, and DA07215). The authors wish to acknowledge the excellent support by Mrs. Michelle Cyr during the preparation of this manuscript.

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