Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

Abstract

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A_2A and dopamine D₂ receptors (R). Stimulation of A_2AR inhibits and blockade of A_2AR enhances D₂R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D₂R via its interaction with A_2AR. Reciprocal A_2AR/D₂R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A_2AR and D₂R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor-receptor interactions within A_2AR/D₂R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson's disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A_2AR/D₂R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.

Keywords: GABAergic enkephalinergic neuron; adenosine A2A receptor; allosteric interaction; dopamine D2 receptor; heteromers; receptor–receptor interactions; striatum.

Figure 1

Metabolic pathways involved in the formation and removal of adenosine. 1 = Oxidative phosphorylation (and creatine kinase), 2 = Energy-consuming processes, 3 = Adenylate kinase, 4 = Apyrase, 5 = Adenylate cyclase, 6 = Phosphodiesterase, 7 = 5′-Nucleotidase, 8 = S-adenosyl homocysteine hydrolase, 9 = Adenosine kinase, 10 = Adenosine deaminase, 11 = Purine phosphorylase, 12 = Xanthine oxidase. ATP = adenosine 5’-triphosphate, ADP = adenosine 5’-diphosphate, AMP = adenosine 5’-monophosphate, cAMP = 3’.5’-cyclic adenosine monophosphate.

Figure 2

Schematic drawing of the direct and indirect pathways for motor control. Solid and faded lines represent direct and indirect pathways, respectively. Blue lines represent excitatory connections and red lines represent inhibitory connections. Pu = putamen, Gpe = globus pallidus externus, Gpi = globus pallidus internus, STN = subthalamic nucleus, SNc = substantia nigra pars compacta, VA/VL = ventral anterior/ventral lateral thalamic nucleus. Created with BioRender.com.

Figure 3

Chemical structures of the A_2A antagonist XCC (A) and the D₂ agonist PPHT-NH2 (B). By attaching a linker to the atomic positions indicated by the arrowheads, a bivalent ligand for A_2AR/D₂R heteromers can be created [392].

Figure 4

Conjugation of dopamine with the A2A antagonist 7-amino-5-(aminomethyl)-cyclohexylmethyl-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a]-1,3,5-triazine trifluoroacetate via a succinate spacer, to obtain the prodrug DP-L-A2AANT, a bivalent ligand [394].

Figure 5

Conjugation of the adenosine A_2AR antagonist ZM241385 (A) and the dopamine D₂ agonist ropinirole (B) to form a heterobivalent ligand (C). Dual action drugs can be prepared by using cyclic (D) or non-cyclic (E) spacers, and the latter may contain an ionizable tertiary amine [395].