G-protein coupled receptors bivalent ligands and drug design

Abstract

G-protein coupled receptors (GPCR) represent a large family of receptors, which have been and still are targets of choice for drug discovery. Among the different tools offered to medicinal chemists to design potent and selective GPCR agonists or antagonists, the bivalent-ligand approach (which consists of bridging two pharmacophores in a single ligand) has proven to be, in many cases, valuable to improve potency, selectivity, intrinsic activity and in vivo profile of the corresponding monomer. This review will focus on GPCR ligands in drug research with particular emphasis on the most recent progress in the field.

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

“…Halazy et al (92) have successfully conjugated two identical sumatriptans (5-HT1B agonist) together to obtain an orally active drug that could induce a stronger hypothermia effect than sumatriptan itself. It is surprising that such a drug was able to cross the blood-brain barrier in spite of its elevated molecular weight, polar surface area, and number of hydrogen-bond donors, indicating that an active transport is probably involved.…”

Discovery of a Competitive Apelin Receptor (APJ) Antagonist

“…[7] This mutant, however, exhibits similar binding affinity and agonist function to the natural apelin peptide in vitro, [3] which suggests that it is a competitive agonist at APJ. ALX40-4C (AcNH-(d-Arg) 9 -COOH) [8] is an antagonist of both the chemokine receptor CXCR4 and APJ. CXCR4/APJ-mediated cell membrane fusion is inhibited in a dose-dependent manner.…”

“…The approach taken in developing a novel series of high-affinity APJ binders that might lead to the discovery of competitive antagonists for this receptor employed the bivalent ligand approach, a method that has shown some success in the discovery of novel GPCR ligands, [9] but to our knowledge had not been applied to the apelin system. This strategy involves the design of a single molecule that incorporates two monomer units comprising the pharmacophore features necessary for affinity, linked through a spacer.…”

“…By using a bivalent ligand approach, we have designed compounds with two 'affinity' motifs and a short series of linker groups with different conformational and non-bonded interaction properties. One of these, cyclo(1-6)CRPRLC-KHcyclo (9)(10)(11)(12)(13)(14)CRPRLC is a competitive antagonist at APJ. Radioligand binding in CHO cells transfected with human APJ gave a K i value of 82 nm, competition binding in human left ventricle gave a K D value of 3.2 mm, and cAMP accumulation assays in CHO-K1-APJ cells gave a K D value of 1.32 mm.…”

Synthesis and TGF‐β Receptor Binding Inhibition of Multibranched Compounds

“…In the opposite way to their monomeric counterpart, they could have a better antagonist activity by increasing the ligand local concentration in the surrounding of receptors. Numerous examples show that dimerisation of a ligand often induces potential and/or selectivity of biological responses [2]. This strategy has been successfully applied to a large number of peptide hormones such as gastrin, enkephalins [3,4], neurokinins [5], substance P [6], bradykinin [7,8], erythropoïetin [9,10] and serotonin [11].…”