PSNCBAM-1 - CAS 877202-74-9
Category: Inhibitor
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Molecular Formula:
C22H21ClN4O
Molecular Weight:
392.88
COA:
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Targets:
Cannabinoid Receptor
Description:
PSNCBAM-1 is an allosteric, non-competitive antagonist of CB-1 (IC50= 45 and 209 nM) with hypophagic effects in vivo, potentially an anti-obesity agents.
Purity:
≥99% by HPLC
Synonyms:
N-(4-Chlorophenyl)-N'-[3-[6-(1-pyrrolidinyl)-2-pyridinyl]phenyl]urea; PSNCBAM-1; PSNCBAM 1; PSNCBAM1
Storage:
Store in a cool and dry place (or refer to the Certificate of Analysis).
MSDS:
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InChIKey:
HDAYFSFWIPRJSO-UHFFFAOYSA-N
InChI:
InChI=1S/C22H21ClN4O/c23-17-9-11-18(12-10-17)24-22(28)25-19-6-3-5-16(15-19)20-7-4-8-21(26-20)27-13-1-2-14-27/h3-12,15H,1-2,13-14H2,(H2,24,25,28)
Canonical SMILES:
C1CCN(C1)C2=CC=CC(=N2)C3=CC(=CC=C3)NC(=O)NC4=CC=C(C=C4)Cl
1.Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution.
Nguyen T;German N;Decker AM;Langston TL;Gamage TF;Farquhar CE;Li JX;Wiley JL;Thomas BF;Zhang Y J Med Chem. 2017 Sep 14;60(17):7410-7424. doi: 10.1021/acs.jmedchem.7b00707. Epub 2017 Aug 18.
Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [;35;S]GTP-γ-S binding while enhancing [;3;H]CP55,940 binding to the CB1 receptor. Structure-activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.
2.The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB
Gamage TF;Farquhar CE;Lefever TW;Thomas BF;Nguyen T;Zhang Y;Wiley JL Neuropharmacology. 2017 Oct;125:365-375. doi: 10.1016/j.neuropharm.2017.08.008. Epub 2017 Aug 10.
While allosteric modulators of the cannabinoid type-1 receptor (CB;1;) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB;1; allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB;1;, blocking THC's effects in vitro and in vivo, highlighting the potential of CB;1; allosteric modulators for treatment of cannabis intoxication. We investigated the pharmacological effects of PSNCBAM-1 and two structural analogs, RTICBM-15 and -28, as well as pregnenolone, in both signaling and behavioral assays including [;35;S]GTPγS binding, the cannabinoid tetrad and drug discrimination. While the CB;1; allosteric modulator PSNCBAM-1 attenuated THC-induced anti-nociception and its structural analog RTICBM-28 reduced THC's potency in drug discrimination, most cannabinoid effects in mice were unaffected. In contrast to the mouse studies, PSNCBAM-1 and analogs insurmountably antagonized CP55,940- and THC-stimulated [;35;S]GTPγS binding and exhibited negative binding cooperativity with [;3;H]SR141716 with similar apparent affinities.
3.Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB
Khurana L;Fu BQ;Duddupudi AL;Liao YH;Immadi SS;Kendall DA;Lu D J Med Chem. 2017 Feb 9;60(3):1089-1104. doi: 10.1021/acs.jmedchem.6b01448. Epub 2017 Jan 19.
The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB;1;) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB;1; antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB;1; ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB;1; orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via β-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB;1; allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.
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CAS 877202-74-9 PSNCBAM-1

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