Adenosine A_2A Receptor-Antagonist/Dopamine D₂ Receptor-Agonist Bivalent Ligands as Pharmacological Tools to Detect A_2A-D₂ Receptor Heteromers

Abstract

Adenosine A(2A) (A(2A)R) and dopamine D(2) (D(2)R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D(2)R agonist and an A(2A)R antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D(2)R heteromers. Bivalent ligands with shorter linkers bound to D(2)R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D(2)R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D(2)R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.

G-protein-coupled receptor heteromer dynamics

“…Examples of this approach are found in the work of Whistler, Franco and colleagues. The Whistler group showed that the agonist 6Ј-guanidinoaltrindole (6Ј-GNTI) selectively activates the heterodimer of -and -opioid receptors to produce an analgesic response in mice (Waldhoer et al, 2005), and the Franco group designed hetero-bivalent ligands containing both a D 2 R agonist and an A 2A R antagonists coupled by chemical spacer to target the A 2A R-D 2 R hetrodimer as a new strategy for the treatment of Parkinson's disease (Soriano et al, 2009). …”

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

“…Although the functional significance and consequences of a number of such pairings, including those between dopamine D 1 and D 2 (10 -12) and -and ␦-opioid (13-16) receptor subtypes, have been explored, the relevance of other pairings has been studied less extensively. With notable exceptions such as interactions between adenosine and dopamine receptor subtypes (17,18), this is particularly true of pairings between GPCRs for which the endogenous agonist ligands are distinct. Despite this, a number of commentators have discussed the potential for such heteromers to respond to ligands in unique ways and to offer the potential as novel sets of drug targets (3, 19 -22).…”

Adenosine A2A Receptor Antagonists in Drug Development

“…The merging of pharmacophores for an agonist at one receptor (D 2 ) and an antagonist at another receptor (A 2A ) is difficult or even impossible. Therefore all published approaches have connected two pharmacophores, one for each receptor, by linkers of different length (Dalpiaz et al 2012;Jorg et al 2015;Soriano et al 2009). Compound 27 is a dopamine prodrug which releases dopamine after amide hydrolysis (Fig.…”