title: Correlation between low/high affinity ratios for 5-HT(1A) receptors and intrinsic activity.
abstract: G protein-coupled receptors exist in G protein-coupled and -uncoupled forms that exhibit high and low affinity for agonists, respectively. Consequently, affinity differences of a compound for the high vs. the low affinity state of a receptor have been used to estimate its intrinsic activity at that receptor. We examined the affinity of a series of compounds for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor sites labeled with 0.2 nM [3H](+/-)-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) (high affinity), or with 0.25 nM [3H]4-(2'-methoxy-)-phenyl-1-[2'-(N-2"-pyridyl)-p-fluorobenzamido] eth yl-piperazine ([3H]p-MPPF) in the presence of 100 microM guanylylimidodiphosphate (Gpp(NH)p) (low affinity) in rat hippocampal membranes. For a variety of 5-HT(1A) receptor ligands, the low/high affinity ratio (ranging from 110 for 5-HT to 0.12 for spiperone) was in good agreement with their reported intrinsic activity. Positive rank correlations were found between low/high affinity ratios and intrinsic activities (E(max) values) reported in the literature. The high efficacy 5-HT(1A) receptor agonists, 1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)piperaz ine (S-14506) and dihydroergotamine, however, had similar, high affinity for both G protein-coupled and -uncoupled forms of the receptor. The Hill coefficients for both compounds were markedly higher than 1.0, suggesting that positive cooperativity could be responsible for the unexpected results. The 5-HT(1A) receptor agonist activity of dihydroergotamine and S-14506, assessed by measuring the inhibition of forskolin-stimulated cAMP accumulation, was blocked completely by pertussis toxin, reinforcing the suggested involvement of an inhibitory G protein in their effects. Taken together, the results suggest that, although the low/high affinity ratio of a ligand for 5-HT(1A) receptors generally covaries with its intrinsic activity, dihydroergotamine and S-14506 may interact with 5-HT(1A) receptors in a manner different from that of other 5-HT(1A) receptor agonists. Their effects, however, appear to be G(i) protein-dependent.
authors.affiliation: Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106, Castres, France. marie.bernadette.assie@pierre-fabre.com
authors.forename: M B
authors.initials: MB
authors.lastname: Assié
authors.forename: C
authors.initials: C
authors.lastname: Cosi
authors.forename: W
authors.initials: W
authors.lastname: Koek
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000631:Aminopyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C099463:4-(2' methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go