A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

Abstract

Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.

Structure-Activity Analysis of Biased Agonism at the Human Adenosine A3 Receptor

“…The SAR of biased agonism has been investigated previously at a number of GPCRs, including the AT 1 R and dopamine D 2 receptors (Holloway et al, 2002;Chen et al, 2012;Shonberg et al, 2013); however, bias at the A 3 AR remains a relatively new concept (Gao and Jacobson, 2008). The current study took advantage of the rich SAR surrounding the A 3 AR to gain insights into the structural determinants that govern bias at this receptor.…”

Molecular Determinants of Allosteric Modulation at the M1 Muscarinic Acetylcholine Receptor

“…The lowest energy conformation of this pose was selected and subjected to an energy minimization using MMFF94X force field. Molecular dynamics (MD) simulations of the final complex was performed with NAMD2.9 (27) package using the protocol described previously (28).…”

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

“…An advantage of the operational model as applied to SAR is that it can almost always be fitted to experimentally derived data to provide estimates of some, or all, of its parameters with regards both to allosteric modulators (Aurelio et al, 2009;Gregory et al, 2012;Valant et al, 2012a;Huynh et al, 2013;Mistry et al, 2013) and biased agonists (Tschammer et al, 2011b;Shonberg et al, 2013;Szabo et al, 2014). Table 1 illustrates an example of allosteric modulator SAR determined through analysis of the effects of various thienopyridine modulators on acetylcholine-mediated ERK1/2 phosphorylation at the M 4 mAChR.…”