Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators.
J Med Chem
; 62(21): 9806-9823, 2019 11 14.
Article
in En
| MEDLINE
| ID: mdl-31596583
ABSTRACT
We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB1) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [35S]GTPγS binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [35S]GTPγS binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenylurea Compounds
/
Receptor, Cannabinoid, CB1
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2019
Type:
Article
Affiliation country:
United States