Rational design of dualsteric GPCR ligands: quests and promise

Abstract

Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation.

Structure–Activity Study of N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor

“…The use of flexible linkers has also been used to explore the distance between such orthosteric and allosteric sites or even between orthosteric sites within GPCR receptor dimers. 9,11,45,46 Our findings demonstrate that flexibility in the spacer region is beneficial for enhancements to functional affinity relative to the rigid cyclohexylene spacer. This result could be expected given the ability for ligands to occupy two binding sites simultaneously could be more energetically favourable with a flexible linker.…”

“…8 More recently, concomitantly targeting both orthosteric and allosteric sites with bitopic ligands, in which allosteric and orthosteric pharmacophores have been linked together, has been explored as a means of developing more selective GPCR ligands. [9][10][11] SB269652 (1) 12,13 was recently described as the first small molecule negative allosteric modulator of the D 2 R. 13 This was somewhat surprising, given that 1 contains structural features of numerous orthosteric D 2 -like receptor ligands. 12,[14][15][16] Indeed, the 1,2,3,4-tetrahydroisoquinoline (THIQ) 'head' group of 1 contains a basic tertiary amine that is expected to form a salt bridge with the conserved aspartate (Asp 3.32 , Ballosteros-Weinstein nomenclature 17 ) of aminergic GPCRs, and would thus compete with the binding of dopamine.…”

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

“…Although such an exosite still awaits experimental confirmation, it is of note that a similar bi/multivalency is well known to increase the affinity/'avidity' and long-lasting binding of antibodies and of many other biological interactions [56]. This concept is well established in biological therapeutics and is increasingly relied upon to generate highly effective drugs and tracers [57][58][59][60]. An essential feature of the current models …”

Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

“…This property was observed with our agonist, VCP746, at the A 1 AR and previously, the bitopic antagonist, THRX-160209, at the M 2 muscarinic acetylcholine receptor (49) but not the bitopic agonists LUF6258 at the A 1 AR (28) or hybrid 2 at the M 2 receptor (50). Possible reasons for the failure to improve affinity in these cases include a mismatch between the constituent orthosteric and allosteric pharmacophores (e.g., orthosteric agonist plus allosteric antagonist), a lack of concomitant engagement of both binding sites (e.g., suboptimal linker length), or a deleterious effect of the linker itself (26,51,52). We noted the latter with VCP900 (adenosine plus linker), which was less potent than adenosine itself.…”