Molecules of the
Rimonabant: A new class of drug to fight obesity
Obesity and tobacco abuse, widely recognised as serious induced by cannabinoid receptor agonists. It powerfully
health hazards, are increasing in prevalence. Obesity is reduces food intake and increases energy expenditure. It
associated with numerous metabolic complications such as modulates the rewarding properties of food by inhibiting the
dyslipidemia, type 2 diabetes and cardiovascular diseases. action of endogenous cannabinoids at specific mesolimbic
Smoking is a high risk factor for hypertension, lung carcinoma areas. It alters the variety of signals of peripheral origin (leptin,
and various other health related problems. The agents that ghrelin and adiponectin) which modulate the neurochemical
have been used for the treatment of obesity include activation of hypothalamic neurons and the state of relative
dexfenfluramine, phentermine, sibutramine and orlistat. energy balance. Rimonabant also inhibits the enzymes involved
Currently, the options for smoking cessation are nicotine in lipogenesis. Many rodent model studies have demonstrated
patches, gum, lozenges and bupropion. As many of these drugs a memory enhancing effect due to rimonabant use. Certainly,
have serious adverse effects or are unsuitable for maintenance more information will become available as the drug completes
therapy, the search for a novel drug continues. phase III trials.
Rimonabant appears to be a promising drug in an entirely
new class called selective cannabinoid (CB1) receptor
antagonists. Recent studies have demonstrated the beneficial A number of preclinical trials have been conducted on the
effects of rimonabant in tackling obesity, smoking cessation effects of rimonabant in rodent models. The trials
and metabolic syndrome. The drug may be approved for demonstrated that rimonabant treatment was associated with
treatment of obesity and smoking cessation. Ongoing studies a reduction in intake of highly palatable as well as normal
may provide information on its other clinical uses. foods in rats. Wiley et al  demonstrated that CB1 antagonist
rimonabant dependently decreased food consumption at doses
which did not affect motor activity in mice. These trials
Rimonabant (SR141716) is a neurokinin-3 antagonist and suggested that rimonabant may affect the actions of
selective cannabinoid (CB1) receptor antagonist currently being endogenous cannabinoids in regulating appetite, or it may
researched and developed under the proprietary name, directly affect feeding behaviour. In another study, rodents were
Acomplia, by Sanofi-Aventis. The chemical name is N-piperino put on a high fat diet to develop obesity, increase energy intake
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3 and insulin resistance. During a five- week treatment period,
carboxamide. rimonabant resulted in 48% reduction of food and 20%
reduction in body weight. In addition, it helped in correcting
Mechanism of action
Rimonabant is the first in a new class of agents that act by
selectively blocking the cannabinoid-1 receptors with resultant
central and metabolic peripheral effects, thereby decreasing Some phase I/II clinical trials have been completed with
food intake. Evidence currently exists for two types of rimonabant. However, limited information is available
cannabinoid receptors: CB1 and CB2. CB1 receptors are regarding these trails. A randomised, double blind, placebo
present both in the CNS as well as in certain peripheral tissues. controlled crossover study assessed the effect of rimonabant
The areas in which CB1 receptors are most dense are thought on hunger, satiety, food consumption and body weight in obese
to deal with cognition, motor function and movement.  humans and showed a reduction in their food intake and body
Rimonabant is reported to possess a 1000-fold higher affinity weight.
for the CB1 receptor than CB2 receptor. It shows high affinity The results of phase III studies called RIO (Rimonabant in
for the centrally located cannabinoid receptor, while displaying obesity)Europe, RIO-North America and RIO-Lipids, comparing
low affinity for the peripherally located receptor. Additionally, rimonabant 5, 20 mg and placebo, have indicated significantly
it has little or no affinity for non-cannabinoid receptors. more weight loss with rimonabant. (The studies were
prospective, randomised, international, multicentre, double
blind, placebo-controlled trials.) The RIO-Lipids and RIO-
Rimonabant has demonstrated a long duration of action (8 Europe studies showed that the average loss of weight at 12
hours) and good oral bioavailability.  Currently, limited months was 6.9 and 8.6 kg, respectively, with rimonabant 20
information has been published regarding rimonabant’s mg/day; 3.1 and 4.8 kg, respectively, with rimonabant 5 mg/
pharmacokinetic parameters. day.[11,12] The RIO-North America trial was a two-year study
Functional in vitro and in vivo studies showed that that enrolled 3040 obese people throughout USA and Canada.
rimonabant is able to antagonise the pharmacologic effects The investigators found that those who received the highest
220 Indian J Pharmacol | June 2006 | Vol 38 | Issue 3 | 220-21
Molecules of the Millennium
dose of rimonabant (20 mg) lost >5% of their body weight, trials of this exciting drug are required to establish its long
while one-third of them lost >10% of their body weight. term therapeutic implications.
The results also showed an increase in HDL-C levels with a
decrease in atherogenic LDL-C levels. The incidence of
J. Singh, S. Budhiraja
metabolic syndrome decreased by nearly one-third and insulin Department of Pharmacology,
sensitivity was reported as greatly improved. Pt. B. D. Sharma PGIMS,
Rimonabant’s role in smoking cessation will be evaluated Rohtak - 124001, Haryana. India
in STRATUS-US, STRATUS-EU, STRATUS-WW (prospective, E-mail: email@example.com
randomised, multicentre, double blind, placebo-controlled)
trials.  Preliminary results of these trials showed that
treatment with rimonabant greatly increases the likelihood of References
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