title: Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 1. Identification of the 4-quinolinecarboxamide framework.
abstract: A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds 33-76, prompted by chemical modifications of the prototype 4, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure-activity relationships (SARs) have been established. From SARs, (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding Ki = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding Ki = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding Ki = > 100 microM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a Kb = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.
authors.affiliation: Department of Chemistry, SmithKline Beecham S.p.A. Milano, Italy.
authors.forename: G A
authors.initials: GA
authors.lastname: Giardina
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
authors.forename: C
authors.initials: C
authors.lastname: Farina
authors.forename: A D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: M
authors.initials: M
authors.lastname: Grugni
authors.forename: L F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: D B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: R
authors.initials: R
authors.lastname: Rigolio
authors.forename: M
authors.initials: M
authors.lastname: Luttmann
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D006801:Humans; D006860:Hydrogen Bonding; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism; D011817:Rabbits; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D011994:Recombinant Proteins; C106585:SB 218795; C054724:senktide; D013373:Substance P