Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands

Abstract

G-protein-coupled receptors (GPCRs) represent the largest family of membrane proteins involved in cellular signal transduction and are activated by various different ligand types including photons, peptides, proteins, but also small molecules like biogenic amines. Therefore, GPCRs are involved in diverse physiological processes and provide valuable drug targets for numerous diseases. Emerging body of evidence suggests that GPCRs exist as monomers or cross-react forming dimers and higher-ordered oligomers. In this Perspective we will review current biochemical and biophysical techniques to visualize GPCR dimerization, functional consequences of homo- and heterodimers, and approaches of medicinal chemists to target these receptor complexes with homo- and heterobivalent ligands.

G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

“…Other receptor-heteromer selective compounds obtained by the DDS approach include the putative D 1 -D 2 receptor heteromer compound SKF-83959 [6-chloro-7, 8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] (Rashid et al, 2007; but see Chun et al, 2013) and clozapine, which not only acts as a potent serotonin 5-HT 2A receptor antagonist but also increases the intrinsic efficacy of glutamate in the mGlu 2 -5-HT 2A receptor heteromer (Fribourg et al, 2011). DDS using bivalent ligands constitutes another approach for targeting receptor-heteromers (recently reviewed in Hiller et al, 2013). A bivalent ligand consists of two pharmacophoric entities linked by an appropriate spacer.…”

Phospholipid Bicelles Improve the Conformational Stability of Rhodopsin Mutants Associated with Retinitis Pigmentosa

“…As a model of GPCRs, Rho has been extensively studied, and since the first report of its crystal structure, several GPCRs structures have been solved by X-ray crystallography [1][2][3][4][5] . Rho is found in the rod outer segment (ROS) membranes of the photoreceptor cells of the retina where it is embedded in the lipid bilayer surrounded by ~65-70 phospholipids per protein molecule [6][7][8][9] .…”

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

“…There are several papers describing the "bivalent ligand" approach, which have performed good results in terms of affinity and selectivity, [18][19][20][21] and to the best of our knowledge, in the field of the 5-HT 7 /5-HT 1A receptor ligands it was used only once before. 22 Given the importance of the 1-arylpiperazine moiety for its affinity to serotoninergic receptors, we have duplicated this template in order to identify homo and hetero bis-piperazine 5-HT 7 R selective ligands.…”