CB1 receptor antagonists: New discoveries leading to new perspectives

E. Kirilly, X. Gonda, G. Bagdy

Research output: Contribution to journalReview article

57 Citations (Scopus)

Abstract

CB1 receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB1 receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB1 receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB1 receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB1 receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB1 receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.

Original languageEnglish
Pages (from-to)41-60
Number of pages20
JournalActa Physiologica
Volume205
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

Fingerprint

Cannabinoid Receptor CB1
rimonabant
sibutramine
Psychiatry
Dexfenfluramine
Anti-Obesity Agents
Endocannabinoids
Precision Medicine
Molecular Models
Therapeutic Uses
Blood-Brain Barrier
Pharmaceutical Preparations
Patient Selection
Statistical Factor Analysis
Anxiety
Obesity
Body Weight
Depression
Therapeutics
Population

Keywords

  • 5-HTTLPR.
  • Anxiety
  • CNR1
  • Depression
  • Personalized medicine
  • Serotonin transporter

ASJC Scopus subject areas

  • Physiology

Cite this

CB1 receptor antagonists : New discoveries leading to new perspectives. / Kirilly, E.; Gonda, X.; Bagdy, G.

In: Acta Physiologica, Vol. 205, No. 1, 01.01.2012, p. 41-60.

Research output: Contribution to journalReview article

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