One for the Price of Two…Are Bivalent Ligands Targeting Cannabinoid Receptor Dimers Capable of Simultaneously Binding to both Receptors?

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• 作者：Michelle Glass¹ ; ^{m.glass@auckland.ac.nz" class="auth_mail" title="E-mail the corresponding author} ; Karan Govindpani¹ ; Daniel P. Furkert² ; Dow P. Hurst³ ; Patricia H. Reggio³ ; Jack U. Flanagan¹ ; ⁴
• 关键词：G-protein-coupled receptors ; oligomers ; dual-acting ligands ; heteromer
• 刊名：Trends in Pharmacological Sciences
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：37
• 期：5
• 页码：353-363
• 全文大小：2899 K

文摘

Bivalent ligands bridging two G-protein-coupled receptors (GPCRs) provide valuable pharmacological tools to target oligomers. The success of therapeutically targeting the cannabinoid CB₁ receptor has been limited, in part due to its widespread neuronal distribution. Therefore, CB₁ ligands targeting oligomers that exhibit restricted distribution or altered pharmacology are highly desirable, and several bivalent ligands containing a CB₁ pharmacophore have been reported. Bivalent ligand action presumes that the ligand simultaneously binds to both receptors within the dimeric complex. However, based on the current understanding of CB₁ ligand binding, existing bivalent ligands are too short to bind both receptors simultaneously. However, ligands with longer linkers may not be the solution, because evidence suggests that ligands enter CB₁ through the lipid bilayer and, thus, linkers are unlikely to exit the receptor through its external face. Thus, the entire premise of designing bivalent ligands targeting CB₁ must be revisited.