Mastering tricyclic ring systems for desirable functional cannabinoid activity

Abstract

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [35S]GTP-γ-S assays. The structure-activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor–selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment.

Characterization of the synthetic cannabinoid MDMB-CHMCZCA

“…The structure of MDMB-CHMCZCA, a semi-systematic name for m ethyl d i m ethyl b utanoate- c yclo h exyl m ethyl c arba z ole c arbox a mide, is related to the structure of MDMB-CHMICA, but contains an N -alkylated carbazole instead of an indole core. Carbazoles are the core structures of an emerging group of cannabimimetics [11–12]. Several N -alkylated carbazole-3-carboxamides were patented by Diaz, Diaz, and Petrov in 2012 as tricyclic cannabinoid receptor modulators, explored against neuropathic pain [13].…”

CB2Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

“…Thus, internalization of a GPCR in response to a ligand can be considered a form of signaling. CB 2 receptors exhibit variable internalization in response to an agonist, with some agonists promoting marked internalization and others being inactive (Grimsey et al, 2011;Atwood et al, 2012b;Petrov et al, 2013).…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…In cases of low sequence similarity, multiple sequence alignment might help in improving the quality of the final model [45][46][47], though it should be stressed that a correct sequence alignment is necessary -though hardly sufficient-to develop reliable homology models. Regarding the construction of the crude model, multiple-template approaches have also been used to model the target "by pieces" [48][49][50][51][52].…”

“…Later, a benchmarking study for existing GPCRs was published [41] (see next section). The ligand steered method was also used to rationalize structure-activity relationships (SAR) data of agonists and antagonists binding to the cannabinoid CB2 receptor [49,51,68].…”