title: Functional partial agonism at ionotropic excitatory amino acid receptors.
abstract: (RS)-2-Amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid (APPA), which is an analogue of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), shows the characteristics of a partial AMPA receptor agonist. Since (S)-APPA is a full AMPA agonist and (R)-APPA a competitive antagonist, the partial agonism observed for APPA, which is a 1:1 mixture of (S)- and (R)-APPA, is only apparent. These observations have prompted comparative pharmacological studies of different molar ratios of a series of AMPA and N-methyl-D-aspartic acid (NMDA) agonists and respective competitive antagonists, and of these agonists in the presence of fixed concentrations of antagonist. Using the rat cortical wedge preparation, the latter series of experiments showed the expected rightward parallel shifts of the dose-response curves. The former type of experiments, on the other hand, produced dose-response curves at different levels of maximal response, depending on the molar ratios of agonist and antagonist used. This phenomenon, which is in agreement with the theory for competitive receptor interaction, has been termed functional partial agonism, a new pharmacological concept of potential therapeutic utility. These results were obtained using AMPA, the AMPA agonist (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), the competitive AMPA antagonists (RS)-2-amino-3-(3-carboxymethoxy-5-methyl-4-isoxazolyl)propionic acid (AMOA) and 6-nitro-7-sulfamoylbenzo[f] quinoxalin-2,3-dione (NBQX), NMDA, and the competitive NMDA antagonist (RS)-3-(2-carboxy-4-piperazinyl)propyl-1-phosphonic acid (CPP).
authors.affiliation: Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Ebert
authors.forename: U
authors.initials: U
authors.lastname: Madsen
authors.forename: K K
authors.initials: KK
authors.lastname: Søby
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D008959:Models, Neurological; D016202:N-Methylaspartate / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015226:Dinucleoside Phosphates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D011422:Propionates; D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C066116:2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid; C012276:diadenosine pyrophosphate; C086714:2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid; D016202:N-Methylaspartate; D000409:Alanine