In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569.

Abstract:

:Several allosteric modulators (AMs) of the CB1 receptor have been characterized in vitro, including Org27569, which enhances CB1-specific binding of [H]CP55,940, but behaves as an insurmountable CB1-receptor antagonist in several biochemical assays. Although a growing body of research has investigated the molecular actions of this unusual AM, it is unknown whether these actions translate to the whole animal. The purpose of the present study was to determine whether Org27569 would produce effects in well-established mouse behavioral assays sensitive to CB1 orthosteric agonists and antagonists. Similar to the orthosteric CB1 antagonist/inverse agonist rimonabant, Org27569 reduced food intake; however, this anorectic effect occurred independently of the CB1 receptor. Org27569 did not elicit CB1-mediated effects alone and lacked efficacy in altering antinociceptive, cataleptic, and hypothermic actions of the orthosteric agonists anandamide, CP55,940, and Δ-tetrahydrocannabinol. Moreover, it did not alter the discriminative stimulus effects of anandamide in FAAH-deficient mice or Δ-tetrahydrocannabinol in wild-type mice in the drug discrimination paradigm. These findings question the utility of Org27569 as a 'gold standard' CB1 AM and underscore the need for the development of CB1 AMs with pharmacology that translates from the molecular level to the whole animal.

journal_name

Behav Pharmacol

journal_title

Behavioural pharmacology

authors

Gamage TF,Ignatowska-Jankowska BM,Wiley JL,Abdelrahman M,Trembleau L,Greig IR,Thakur GA,Tichkule R,Poklis J,Ross RA,Pertwee RG,Lichtman AH

doi

10.1097/FBP.0000000000000027

subject

Has Abstract

pub_date

2014-04-01 00:00:00

pages

182-5

issue

2

eissn

0955-8810

issn

1473-5849

pii

00008877-201404000-00010

journal_volume

25

pub_type

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