title: Pharmacological assessment of spantide II analogues.
abstract: We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5-7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than spantide II in causing histamine release from rat peritoneal mast cells.
authors.affiliation: Department of Pharmacology, University of Lund, Sweden.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.forename: D M
authors.initials: DM
authors.lastname: Feng
authors.forename: Y L
authors.initials: YL
authors.lastname: Wang
authors.forename: S R
authors.initials: SR
authors.lastname: Tung
authors.forename: K
authors.initials: K
authors.lastname: Wong
authors.forename: G R
authors.initials: GR
authors.lastname: Strichartz
authors.forename: K
authors.initials: K
authors.lastname: Folkers
authors.forename: R
authors.initials: R
authors.lastname: Håkanson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D007498:Iris / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011817:Rabbits; D011892:Rana catesbeiana; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D015320:Tachykinins; C065446:spantide II; D013373:Substance P