Synthesis and Pharmacological Evaluation of Dual Acting Ligands Targeting the Adenosine A_2A and Dopamine D₂ Receptors for the Potential Treatment of Parkinson’s Disease

Abstract

A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

“…For each of the identified templates, we have indicated the general mono‐ or multitarget profile, the most representative molecules, and corresponding advantages and disadvantages. During the reviewing process of this work, additional examples of dual‐acting ligands (A 2A AR/D2) have been reported …”

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

“…Since Portoghese and coworkers pioneered bivalent ligands targeting GPCRs, 46 bivalent ligands have been developed for various GPCR systems including the opioid, 46-50 serotonin, 51-53 adenosine, 54 cannabinoid, 55-56 chemokine, 57 dopamine, 58 and melanocortin receptors. 25, 59-69 Bivalent ligands have been demonstrated to have a variety of different pharmacological effects as compared to their monovalent counterparts including: increasing or decreasing binding affinity, 52, 58, 64 positively or negatively changing functional responses, 53-55, 59, 70 altering receptor subtype selectivity, 47, 58 changing receptor trafficking, 71-73 and creating tissue selectivity. 50, 74 Due to these unique characteristics, bivalent ligands offer distinct advantages over the classical monomeric approach.…”

Safety issues of compounds acting on adenosinergic signalling

“…Development of partial A 1 AdR agonists is being fostered to attenuate heart rate changes that are typical for adenosine . New integrated dual acting ligands are also being developed, for example dual A 2A AdR antagonists/dopamine D 2 agonist for PD treatment . Due to dynamic, allosteric nature of AdRs (the most studied being the A 2A AdR), new allosteric enhancers represent a promising alternative to basic adenosine derivatives .…”

“…[135] New integrated dual acting ligands are also being developed, for example dual A 2A AdR antagonists/dopamine D 2 agonist for PD treatment. [137] Due to dynamic, allosteric nature of AdRs (the most studied being the A 2A AdR), new allosteric enhancers represent a promising alternative to basic adenosine derivatives. [138,139] They represent a highly selective way of agonism, for example highly selective A 1 AdR thiophene-based allosteric enhancer 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene.…”