Otenabant hydrochloride

Cannabinoid Receptor 1 (CB1) is a membrane protein prevalent in the central nervous system, whose crystallographic structure has recently been solved. Studies will be needed to investigate CB1 complexes with its ligands and its role in the development of new drugs.

Our goal here is to review the studies on CB1, starting with general aspects and focusing on the recent structural studies, with emphasis on the inverse agonists bound structures.

We start with a literature review, and then we describe recent studies on CB 1 crystallographic structure and docking simulations. We use this structural information to depict protein-ligand interactions. We also describe the molecular docking method to obtain complex structures of CB 1 with inverse agonists.

Analysis of the crystallographic structure and docking results revealed the residues responsible for the specificity of the inverse agonists for CB 1. Most of the intermolecular interactions involve hydrophobic residues, with the participation of the residues Phe 170 and Leu 359 in all complex structures investigated in the present study. For the complexes with otenabant and taranabant, we observed intermolecular hydrogen bonds involving residues His 178 (otenabant) and Thr 197 and Ser 383 (taranabant).

Analysis of the structures involving inverse agonists and CB 1 revealed the pivotal role played by residues Phe 170 and Leu 359 in their interactions and the strong intermolecular hydrogen bonds highlighting the importance of the exploration of intermolecular interactions in the development of novel inverse agonists.

Antagonists of peripheral type 1 cannabinoid receptors (CB1) may have utility in the treatment of obesity, liver disease, metabolic syndrome and dyslipidemias. We have targeted analogues of the purine inverse agonist otenabant (1) for this purpose. The non-tissue selective CB1 antagonist rimonabant (2) was approved as a weight-loss agent in Europe but produced centrally mediated adverse effects in some patients including dysphoria and suicidal ideation leading to its withdrawal. Efforts are now underway to produce compounds with limited brain exposure. While many structure-activity relationship (SAR) studies of 2 have been reported, along with peripheralized compounds, 1 remains relatively less studied. In this report, we pursued analogues of 1 in which the 4-aminopiperidine group was switched to piperazine group to enable a better understanding of SAR to eventually produce compounds with limited brain penetration. To access a binding pocket and modulate physical properties, the piperazine was functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a variety of connectors, including amides, sulfonamides, carbamates and ureas. These studies resulted in compounds that are potent antagonists of hCB1 with high selectivity for hCB1 over hCB2. The SAR obtained led to the discovery of 65 (Ki = 4 nM, >1,000-fold selective for hCB1 over hCB2), an orally bioavailable aryl urea with reduced brain penetration, and provides direction for discovering peripherally restricted compounds with good in vitro and in vivo properties.