title: A consideration of the dopamine D2 receptor monomer-dimer equilibrium and the anomalous binding properties of the dopamine D2 receptor ligand, N-methyl spiperone.
abstract: Some discrepancies between experimental results with the two D2 antagonists N-methyl spiperone (NMSP) and raclopride (RAC) have been observed. Among these are the observation that MK-801 increases NMSP binding but not RAC binding: pretreatment with reserpine increases RAC binding but decreases NMSP binding; and that the two ligands yield different values for Bmax. It has been observed that the D2 receptor can exist in both a monomer and dimer form and that a NMSP photolabel ligand binds primarily to the monomer form while a RAC-like photolabel ligand binds both. Using a model of the dimerization in which the equilibrium dissociation constant increases with increasing dopamine (DA) concentration, the free monomer concentration can be shown to go through a maximum value with increasing DA. Using this model with data from a baboon PET study, it can be shown that under certain conditions an increase in binding could be observed. Further research may show that there are clusters of D2 receptors forming oligomers with more than two receptors in which NMSP binds to more sites on clusters with fewer receptors. If increasing DA favors cluster with fewer receptors, an increase in NMSP binding sites may also occur under some circumstances with an increase in DA.
authors.affiliation: Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA. jlogan@bnl.gov
authors.forename: J
authors.initials: J
authors.lastname: Logan
authors.forename: J S
authors.initials: JS
authors.lastname: Fowler
authors.forename: S L
authors.initials: SL
authors.lastname: Dewey
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D019281:Dimerization; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D010215:Papio / Q000502:physiology; D020891:Raclopride / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D013134:Spiperone / Q000031:analogs & derivatives / Q000494:pharmacology*; D014055:Tomography, Emission-Computed
chemical_list: D018492:Dopamine Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D020891:Raclopride; D013134:Spiperone; C039167:3-N-methylspiperone