Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

Abstract

Rimonabant is an inverse agonist specific for cannabinoid receptors and selective for their cannabinoid-1 (CB 1 ) subtype. Although CB 1 receptors are more abundant in the central nervous system, rimonabant has many effects in the periphery, most of which are related to prejunctional modulation of transmitter release from autonomic nerves. However, CB 1 receptors are also expressed in, e.g., adipocytes and endothelial cells. Rimonabant inhibits numerous cardiovascular cannabinoid effects, including the decrease of blood pressure by central and peripheral (cardiac and vascular) sites of action, with the latter often being endothelium dependent. Rimonabant may also antagonize cannabinoid effects in myocardial infarction and in hypotension associated with septic shock or liver cirrhosis. In the gastrointestinal tract, rimonabant counteracts the cannabinoid-induced inhibition of secretion and motility. Although not affecting most cannabinoid effects in the airways, rimonabant counteracts inhibition of smoothmuscle contraction by cannabinoids in urogenital tissues and may interfere with embryo attachment and outgrowth of blastocysts. It inhibits cannabinoid-induced decreases of intraocular pressure. Rimonabant can inhibit proliferation of, maturation of, and energy storage by adipocytes. Among the many cannabinoid effects on hormone secretion, only some are rimonabant sensitive. The effects of rimonabant on the immune system are not fully clear, and it may inhibit or stimulate proliferation in several types of cancer. We conclude that direct effects of rimonabant on adipocytes may contribute to its clinical role in treating obesity. Other peripheral effects, many of which occur prejunctionally, may also contribute to its overall clinical profile and lead to additional indications as well adverse events.

Physical and functional interaction between CB1 cannabinoid receptors and β2‐adrenoceptors

“…In addition, the recent observation that CB 1 receptors are expressed in murine cardiomyocytes (Mukhopadhyay et al. , 2007) suggests that some of the cardiovascular effects of CB 1 receptor inverse agonists (Van diepen et al. , 2008) may be the result of indirect actions on β 2 ‐adrenoceptors in addition to the direct blockade of CB 1 receptors.…”

How reliable are G-protein-coupled receptor antibodies?

“…However, some findings in this issue of the Journal demonstrate that N-and C-terminal-directed antibodies similarly lack specificity as those directed against more conserved receptor domains (Jensen et al 2009;Jositsch et al 2009). Irrespective of such considerations, these problems suggest that many previously published data, including some in this Journal (Otsuka et al 2008;van Diepen et al 2008), may require re-interpretation. This shows that irrespective of a good explanation for the lack of selectivity of many GPCR antibodies, it is important to develop better criteria to accept an antibody as specific for its target.…”

Cannabinoid 1 receptors modulate intestinal sensory and motor function in rat

“…In this study, the effect of the more selective CB 1 antagonist SR 141716A was less pronounced and this difference may only partially be explained by differences in organ bath setup. Considering that SR 141716A and AM251 were both reported to have inverse agonist properties 39,40 and have additional effects at other receptors, 41 our present study emphasizes that properties of CB 1 active compounds need to be carefully characterized prior to drawing definite conclusions. In contrast to our setup of the ascending peristaltic reflex, peristaltic activity seems not to be influenced by SR 141716A, when peristalsis is initiated as a response to intraluminal distension 35 .…”