Dopamine receptors labelled by PHNO
- 1 August 1993
- Vol. 14 (4), 254-262
- https://doi.org/10.1002/syn.890140403
Abstract
Since the high-affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive agonist to label this high-affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's disease. We prepared [3H](+)PHNO from allyl-des-propyl-(+)PHNO. In binding to dopamine receptors in homogenates of canine brain striata, [3H](+)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of [3H](+)PHNO at drug concentrations similar to those inhibiting other [3H]ligands at D2 receptors, but not similar to those acting at D4 receptors. Approximately 90% of the total [3H](+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhibited [3H](+)PHNO binding, suggesting that [3H](+)PHNO was binding primarily to the high-affinity state of dopamine D2 receptors rather than to D3 receptors. The density of the [3H](+)PHNO binding sites was equal to that of [3H]emonapride (or [3H]YM-09151-2), both densities of which were 1.5- to 2-fold higher than that of [3H]spiperone, compatible with the idea that [3H](+)PHNO binds to monomers of D2, while [3H]spiperone binds to dimers of D2. Although [3H](+)PHNO has good selectivity and affinity for the high-affinity state of D2, the [3H]ligand was sensitive to endogenous dopamine, since washing the tissue lowered the dissociation constant. For future in vivo labelling of D2 by an agonist, therefore, it will be essential to search for a related [3H]ligand with an even lower dissociation constant.Keywords
This publication has 27 references indexed in Scilit:
- The cloned dopamine D2 receptor reveals different densities for dopamine receptor antagonist ligands. Implications for human brain positron emission tomographyEuropean Journal of Pharmacology: Molecular Pharmacology, 1992
- Effects of endogenous dopamine on measures of [18F]N‐methylspiroperidol binding in the basal ganglia: Comparison of simulations and experimental results from PET studies in baboonsSynapse, 1991
- Effects of endogenous dopamine on kinetics of [3H]N‐methylspiperone and [3H]raclopride binding in the rat brainSynapse, 1991
- Amphetamine induced decreases in (18F)‐N‐methylspiroperidol binding in the baboon brain using positron emission tomography (PET)Synapse, 1991
- Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neurolepticsNature, 1990
- Sustained-release (+)-PHNO [MK-458 (HPMC)] in the treatment of Parkinson's disease: Evidence for tolerance to a selective D2-receptor agonist administered as a long-acting formulationMovement Disorders, 1990
- Binding of (+)PHNO and other D2-dopamine agonists to D1-dopamine receptors labelled by [3H]SCH 23390Journal of Neural Transmission, 1987
- Complete Conversion of Brain D2 Dopamine Receptors from the High‐ to the Low‐Affinity State for Dopamine Agonists, Using Sodium Ions and Guanine NucleotideJournal of Neurochemistry, 1985
- Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonistsJournal of Medicinal Chemistry, 1984
- The hydroxy-hexanydronaphthoxazines: a new group of very potent and selective dopamine agonistsJournal of Pharmacy and Pharmacology, 1984