title: Structural requirements of 5-hydroxytryptamine-moduline analogues to interact with the 5-hydroxytryptamine1B receptor.
abstract: 5-Hydroxytryptamine-moduline is an endogenous cerebral tetrapeptide that regulates the activity of 5-hydroxytryptamine1B receptors. Direct binding of 5-[3H]hydroxytryptamine-moduline on rat brain homogenate evidenced the existence of two interacting sites for the peptide, very likely corresponding to different conformations of the 5-hydroxytryptamine1B receptor: The peptide first binds to a low-affinity state of the receptor (pIC50 = 7.68+/-0.14) and then induces (or stabilizes) a high-affinity complex (pIC50 = 11.62+/-0.18). This work focuses on the ability of 5-hydroxytryptamine-moduline analogues to recognize the high- and low-affinity sites for 5-hydroxytryptamine-moduline. The results obtained show that the two conformers of the 5-hydroxytryptamine1B receptor have similar but not identical binding pockets for 5-hydroxytryptamine-moduline. These two sites proved to be stereoselective and selective for tetrapeptides and favored the binding of peptides with hydrophobic amino acids in positions 1 and 4, serine in position 2, and a short amino acid in position 3. However, the serine in position 2 seems to be more important for the interaction of the peptide with the low-affinity site than the high-affinity one, which only needs a short hydrophobic amino acid in position 2.
authors.affiliation: Unité de Pharmacologie Neuro-Immuno-Endocrinienne, Institut Pasteur, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Plantefol
authors.forename: J C
authors.initials: JC
authors.lastname: Rousselle
authors.forename: O
authors.initials: O
authors.lastname: Massot
authors.forename: E
authors.initials: E
authors.lastname: Bernardi
authors.forename: A R
authors.initials: AR
authors.lastname: Schoofs
authors.forename: B
authors.initials: B
authors.lastname: Pourrias
authors.forename: R
authors.initials: R
authors.lastname: Ollivier
authors.forename: G
authors.initials: G
authors.lastname: Fillion
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D008297:Male; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C102005:5-HT-moduline; D009479:Neuropeptides; D009842:Oligopeptides; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin