Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

https://pharmrev.aspetjournals.org/content/pharmrev/54/2/161.full.pdf

International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0707442

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

Pharmacology of cannabinoid cb1 and cb2 receptors

Δ9-Tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Δ9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Δ9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Δ9-THC administration. Thus, most, but not all, CNS effects of Δ9-THC are mediated by the CB1 receptor.

https://www.pnas.org/content/pnas/96/10/5780.full.pdf

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

The effects of cannabinoids on the brain

Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (−)-11-OH-Δ8-THC-dimethylheptyl was 80–1150 times more potent than Δ9-THC. Stereospecificity was demonstrated by its (+)- enantiomer which was more than 1400–7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (−)-11-OH-Δ9-THC-DMH was found to be equipotent with (−)-11-OH-Δ8-THC-DMH. The aldehyde (−)-11-oxo-Δ9-THC-DMH was 15–50 times more potent than Δ9-THC. Surprisingly, (−)-11-carboxy-Δ9-THC-DMH was also active, being slightly more potent than Δ9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to Δ9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.

Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.

In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.

S. J. Ward

Papers

Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.

Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212.