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Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6‑Pyrrolidinylpyridinyl Substitution
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 (<b>2</b>). Similar to <b>2</b>, these diarylureas dose-dependently inhibited CP55,940-induced
intracellular calcium mobilization and [<sup>35</sup>S]ÂGTP-γ-S
binding while enhancing [<sup>3</sup>H]ÂCP55,940 binding to the CB1
receptor. Structure–activity relationship studies revealed
that the pyridinyl ring of <b>2</b> could be replaced by other
aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric
modulation. <b>34</b> (RTICBM-74) had similar potencies as <b>2</b> in all in vitro assays but showed significantly improved
metabolic stability to rat liver microsomes. More importantly, <b>34</b> was more effective than <b>2</b> 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