Functionalized Congener Approach to the Design of Ligands for G Protein-Coupled Receptors (GPCRs)

Abstract

Functionalized congeners, in which a chemically functionalized chain is incorporated at an insensitive site on a pharmacophore, have been designed from the agonist and antagonist ligands of various G protein-coupled receptors (GPCRs). These chain extensions enable a conjugation strategy for detecting and characterizing GPCR structure and function and pharmacological modulation. The focus in many studies of functionalized congeners has been on two families of GPCRs: those responding to extracellular purines and pyrimidines-i.e., adenosine receptors (ARs) and P2Y nucleotide receptors. Functionalized congeners of small-molecule as ligands for other GPCRs and non-G protein coupled receptors have also been designed. For example, among biogenic amine neurotransmitter receptors, muscarinic acetylcholine receptor antagonists and adrenergic receptor ligands have been studied with a functionalized congener approach. Adenosine A 1 , A 2A , and A 3 receptor functionalized congeners have yielded macromolecular conjugates, irreversibly binding AR ligands for receptor inactivation and crosslinking, radioactive probes that use prosthetic groups, immobilized ligands for affinity chromatography, and dual-acting ligands that function as binary drugs. Poly(amidoamine) dendrimers have served as nanocarriers for covalently conjugated AR functionalized congeners. Rational methods of ligand design derived from molecular modeling and templates have been included in these studies. Thus, the design of novel ligands, both small molecules and macromolecular conjugates, for studying the chemical and biological properties of GPCRs have been developed with this approach, has provided researchers with a strategy that is more versatile than the classical medicinal chemical approaches.

2-Dialkynyl derivatives of (N)-methanocarba nucleosides: ‘Clickable’ A3 adenosine receptor-selective agonists

“…Compounds 10 , 14 , 19 , and 26 were designed as potential affinity labels of the A 3 AR, but the chemical irreversibility of binding was not tested in the present study. The use of isothiocyanates, 3-isothiazolones, and other electrophilic derivatives to affinity label biopolymers has been described 13,35…”

“…Amide-linked fluorescent 1 and biotin-containing probes 2 and 3 of high A 3 AR affinity and selectivity were designed using a functionalized congener approach based on stepwise chain extension designed to preserve or enhance receptor affinity (Chart 1). 13…”

Enhanced Potency of Nucleotide−Dendrimer Conjugates as Agonists of the P2Y14 Receptor: Multivalent Effect in G Protein-Coupled Receptor Recognition

“…Uridine-5′-diphosphoglucuronic acid and its ethylenediamine adduct were suitable functionalized congeners (50) for coupling to several generations (G2.5–6) of dendrimers (both terminal carboxy and amino) to modulate potency of the intact conjugates. The observed biological activity of the dendrimer conjugates was clearly P2Y 14 receptor-dependent; the control dendrimers 4 and 5 lacking nucleotides were inactive.…”

4-Alkyloxyimino-cytosine nucleotides: tethering approaches to molecular probes for the P2Y6 receptor

“…Although only one fluorescent conjugate 16 showed high potency at the P2Y 6 R, this site on the nucleotide promises to be a general site for derivatization with bulky substituents, including other fluorophores and specialized reporter groups for receptor detection and characterization. 39 A molecular modeling study was carried out to explore the recognition of the agonist 16 in binding to the P2Y 6 R to highlight the key putative interactions between charged groups of a large fluorophore moiety and the outer regions of TM3 in the P2Y 6 R, which evidently enhance the potency of 16 . In conclusion, we have identified the N 4 -benzyloxy group as a structurally permissive region for synthesis of a family of functionalized congeners as fluorescent conjugates and other pharmacological probes for studying the P2Y 6 R. This will enable further drug discovery related to this receptor.…”

“…A functionalized congener approach to ligand derivatization has been explored for a variety of GPCRs, leading to fluorescent probes, 18 affinity labels, cross-linking ligands, and specialized radioactive probes. 39 SAR analyses suggested that the steric constraints of the pharmacophoric binding site of the receptor likely could be circumvented by chain elongation through two specific sites in P2Y 6 R agonists. Thus, we introduced a 4-alkyloxyimino group in the nucleobase, and the terminal phosphate group was extended in γ-ester derivatives of UTP.…”