A wide range of neurotransmitters, polypeptides and inflammatory mediators transduce their signals into the interior of cell by specific interactions with cell-surface receptors that are coupled to G-protein. The most familiar G-protein-coupled receptors are muscarinic receptors, adrenergic receptors, dopaminergic receptors and opioid receptors. A single polypeptide chain of 400-500 residues forms most of these receptors. There are seven hydrophobic regions in the receptor and they correspond to transmembrane α-helices, which are membrane spanning domains. This topology is highly conserved among various members of the family of G-protein coupled receptors. The amino-terminal extracellular domain contains potential N-linked glycosylation sites in most receptors. The carboxyl-terminal is involved in the coupling to G-proteins and contains a cysteine site and phosphorylation site (Thr, Ser) and both are involved in receptor desensitization. In this section of the review we will discuss the development of potent, selective, low molecular weight antagonists of two G-protein coupled receptors (M2 muscarinic receptor and CCR5 chemokine receptor) and their potential therapeutic utilities. The initial leads in both antagonist programs came from in house screening of our sample collections. As expected, most of the initial leads for both programs shared a similar pharmacophore and because of this showed strong affinity to many if not few a other G-protein coupled receptors. The initial significant challenge in both programs in terms of structure-activity studies was not only to optimize the structures for potency but also selectivity versus other subtype receptors. In the M2 antagonist program the selectivity versus M1 and other subtypes was a major challenge. Similarly in the CCR5 antagonist program the selectivity versus M2 was a significant issue to overcome. In this review we will discuss in detail the structure activity relationships that resulted in potent and selective antagonists.
Keywords: CCR5 Receptor, neurotransmitters, polypeptides, glycosylation, muscarinic
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