ORG-27569 - CAS 868273-06-7
Catalog number: 868273-06-7
Category: Inhibitor
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Cannabinoid Receptor
Org 27569 is an allosteric modulator of cannabinoid CB1 receptor, induces a CB1 receptor state that is characterized by enhanced agonist affinity and decreased inverse agonist affinity.
ORG-27569; ORG-27569; ORG-27569.
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1.Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1).
Khurana L;Ali HI;Olszewska T;Ahn KH;Damaraju A;Kendall DA;Lu D J Med Chem. 2014 Apr 10;57(7):3040-52. doi: 10.1021/jm5000112. Epub 2014 Mar 27.
5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type 1 receptor (CB1). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CB1: a critical chain length at the C3-position, an electron withdrawing group at the C5-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B. These significantly impact the binding affinity (KB) and the binding cooperativity (α). A potent CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a KB of 259.3 nM with a strikingly high binding α of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (12f) with a KB of 89.1 nM, which is among the lowest KB values obtained for any allosteric modulator of CB1. These positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced β-arrestin mediated ERK1/2 phosphorylation.
2.Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.
Tham M;Yilmaz O;Alaverdashvili M;Kelly MEM;Denovan-Wright EM;Laprairie RB Br J Pharmacol. 2018 Jul 7. doi: 10.1111/bph.14440. [Epub ahead of print]
BACKGROUND AND PURPOSE: ;We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures.;EXPERIMENTAL APPROACH: ;HEK293A cells expressing either human type 1 cannabinoid (CB;1; ) receptors or CB;2; receptors were treated with CBD or CBD-DMH with or without the CB;1; and CB;2; receptor agonist CP55,940, CB;1; receptor allosteric modulator Org27569 or CB;2; receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB;1; or CB;2; receptors, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB;1; receptors.;KEY RESULTS: ;At CB;1; receptors, CBD was a negative allosteric modulator (NAM), and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB;1; receptors (5TGZ) but shared a binding site with CP55,940 in the agonist-bound model of CB;1; receptors (5XRA). The binding site for CBD-DMH in the CB;1; receptor models overlapped with CP55,940 and Org27569.
3.Effects of the cannabinoid CB₁ receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats.
Jing L;Qiu Y;Zhang Y;Li JX Drug Alcohol Depend. 2014 Oct 1;143:251-6. doi: 10.1016/j.drugalcdep.2014.08.004. Epub 2014 Aug 17.
BACKGROUND: ;Cannabinoid CB1 receptors play an essential role in drug addiction. Given the side effect profiles of orthosteric CB1 antagonism, new strategies have been attempted to modulate this target, such as CB1 receptor allosteric modulation. However, the effect of CB1 allosteric modulation in drug addiction is unknown. The present study examined the effects of the CB1 receptor allosteric modulator ORG27569 on the reinstatement of cocaine- and methamphetamine-seeking behavior in rats.;METHODS: ;Rats were trained to self-administer 0.75 mg/kg cocaine or 0.05 mg/kg methamphetamine in 2-h daily sessions for 14 days which was followed by 7 days of extinction sessions in which rats responded on the levers with no programmed consequences. On reinstatement test sessions, rats were administered ORG27569 (1.0, 3.2, 5.6 mg/kg, i.p.) or SR141716A (3.2 mg/kg, i.p.) 10 min prior to re-exposure to cocaine- or methamphetamine-paired cues or a priming injection of cocaine (10mg/kg, i.p.) or methamphetamine (1mg/kg, i.p.).;RESULTS: ;Both cues and a priming injection of cocaine or methamphetamine significantly reinstated the extinguished active lever responding. Pretreatment with ORG27569 resulted in a dose-related attenuation of both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior.
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CAS 868273-06-7 ORG-27569

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