title: Structure-activity study of neurokinins: antagonists for the neurokinin-2 receptor.
abstract: A series of 21 peptides were synthesized and tested in a variety of isolated organs in order to determine their potential as neurokinin-2 (NK-2) antagonists. The peptides have been tested in the three monoreceptor systems, the dog carotid artery (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3) as well as on other preparations containing NK-2 receptors, such as the rat vas deferens, the hamster urinary bladder, the guinea-pig trachea and the human urinary bladder. Some of the compounds have also been tested on the human isolated bronchus. Three compounds, of which two are linear peptides, Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2, Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg.NH2 and a cyclic one, cyclo[Gln-Trp-Phe-Gly-Leu-Met] have been shown to reduce or eliminate the effects of neurokinin A (NKA) in practically all the preparations containing NK-2 receptors. The first compound was found to be selective for the NK-2 receptor and showed only agonistic or no activity on the other receptor systems, while the second compound showed some antagonistic effects not only on the NK-2 but also on the other systems. The cyclic compound was found to be fairly selective for the NK-2 receptor. The first compound (Ac.Leu-Asp-Gln-Trp-Phe-Gly.NH2) was characterized with respect to its specificity for neurokinins (NK): it was found to be inactive on receptors for acetylcholine, noradrenaline, angiotensin and des Arg9-bradykinin in the rabbit pulmonary artery. Moreover, the compound exerted a competitive type of antagonism on the rabbit pulmonary artery and on the hamster urinary bladder. Although of moderate affinity, the NK-2 receptor antagonists described in this paper provide important tools for pharmacological studies on NK.
authors.affiliation: Department of Pharmacology, Medical School, University of Sherbrooke, Que., Canada.
authors.forename: S
authors.initials: S
authors.lastname: Dion
authors.forename: N
authors.initials: N
authors.lastname: Rouissi
authors.forename: F
authors.initials: F
authors.lastname: Nantel
authors.forename: D
authors.initials: D
authors.lastname: Jukic
authors.forename: N E
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: C
authors.initials: C
authors.lastname: Tousignant
authors.forename: S
authors.initials: S
authors.lastname: Télémaque
authors.forename: G
authors.initials: G
authors.lastname: Drapeau
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.forename: E
authors.initials: E
authors.lastname: Naline
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D008970:Molecular Weight; D015288:Neurokinin A / Q000494:pharmacology*; D015287:Neurokinin B / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D018042:Receptors, Neurokinin-3; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; D018042:Receptors, Neurokinin-3; D017981:Receptors, Neurotransmitter; D015288:Neurokinin A; D015287:Neurokinin B