title: Design of potent dynorphin A-(1-9) analogues devoid of supraspinal motor effects in mice.
abstract: Four analogues of dynorphin (Dyn) A-(1-9) incorporating D-Leu in position 8 alone or in combination with the nonhydrolysable psi [CS-NH] thiopeptide bond surrogate between positions 6 and 7 were tested in vitro for their ability to compete with the binding of selective kappa, mu, and delta opioid ligands, using membrane preparations of guinea pig cerebellum (kappa) and rat brain (mu and delta), for their ability to block the electrically induced contractions of the guinea pig ileum, and for their in vivo antinociceptive (writhing test) and motor (motor dysfunction assay) activities in mice. [D-Leu8]Dyn A-(1-9) displayed an affinity and a selectivity for the kappa opioid receptor that were comparable with those of Dyn A-(1-9). The potencies of [D-Leu8]Dyn A-(1-9) in the guinea pig ileum, writhing, and motor dysfunction assays were markedly enhanced (8-12 fold) compared with those of Dyn A-(1-9). [6 psi 7(CS-NH),D-Leu8]Dyn A-(1-9), [Lys6, 6 psi 7(CS-NH),D-Leu8] Dyn A-(1-9), and [Leu6, 6 psi 7(CS-NH), D-Leu8]Dyn A-(1-9) were somewhat less potent than [D-Leu8]Dyn A-(1-9) in all opioid assays. However, the thiopeptides were more potent analgesics than Dyn A-(1-9)(ED50 of 29.5, 23.9, and 15.5 nmol/mouse, respectively, compared with 90.7 nmol/mouse for Dyn A-(1-9)) and caused little or no motor impairment at analgesic doses.
authors.affiliation: Institut de chimie des substances naturelles, Centre national de la recherche scientifique, Gif-sur-Yvette, France.
authors.forename: H T
authors.initials: HT
authors.lastname: Le
authors.forename: R
authors.initials: R
authors.lastname: Michelot
authors.forename: M
authors.initials: M
authors.lastname: Dumont
authors.forename: V K
authors.initials: VK
authors.lastname: Shukla
authors.forename: M
authors.initials: M
authors.lastname: Mayer
authors.forename: K P
authors.initials: KP
authors.lastname: Nguyen
authors.forename: H
authors.initials: H
authors.lastname: Ruan
authors.forename: S
authors.initials: S
authors.lastname: Lemaire
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D004399:Dynorphins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D000700:Analgesics; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; D014316:Tritium; C069052:CGP 39653; D004399:Dynorphins; D015763:2-Amino-5-phosphonovalerate; C040238:dynorphin A (1-9)