Diarylureas Containing 5-Membered Heterocycles as CB 1 Receptor Allosteric Modulators: Design, Synthesis, and Pharmacological Evaluation

Abstract

Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB 1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB 1 negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB 1 allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB 1 agonist CP55,940 stimulated calcium mobilization and [ 35 S]GTP-γ-S binding. Similar to 1, most compounds showed positive cooperativity by increasing [ 3 H]CP55,940 binding, consistent with the positive allosteric modulator (PAM)-antagonist mechanism. Interestingly, these compounds exhibited differences in ability to increase specific binding of [ 3 H]CP55,940 and decrease binding of the antagonist [ 3 H]SR141716. In saturation binding studies, only increases in [ 3 H]CP55,940 B max , but not K d , were observed, suggesting that these compounds stabilize low affinity receptors into a high affinity state. Among the series, the 2-pyrrolyl analogue (13) exhibited greater potency than 1 in the [ 35 S]GTP-γ-S binding assay and significantly enhanced the maximum binding level in the [ 3 H]CP5,5940 binding assay, indicating greater CB 1 receptor affinity and/or cooperativity.