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.