title: Conformationally constrained tachykinin analogues: potent and highly selective neurokinin NK-2 receptor agonists.
abstract: The design and synthesis of potent and selective neurokinin NK-2 receptor agonists 12 (GR64349) and 31 are described, together with structure-activity relationships for related analogues. Compound 12 (EC50 = 3.7 nM at NK-2 receptors in the rat colon; selectivity > 1000- and > 300-fold with respect to NK-1 and NK-3 receptors, respectively) was derived by incorporation of a Gly-Leu gamma-lactam conformational constraint into the C-terminal region of the neurokinin A octapeptide analogue [Lys3]-NKA(3-10). Compound 31 (EC50 = 15 nM in rat colon) contains a novel fused-bicyclic constraint at the corresponding site in the substance P hexapeptide analogue [Ava6]-SP(6-11).
authors.affiliation: Medicinal Chemistry Department, Glaxo Group Research, Greenford, Middlesex, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Deal
authors.forename: R M
authors.initials: RM
authors.lastname: Hagan
authors.forename: S J
authors.initials: SJ
authors.lastname: Ireland
authors.forename: C C
authors.initials: CC
authors.lastname: Jordan
authors.forename: A B
authors.initials: AB
authors.lastname: McElroy
authors.forename: B
authors.initials: B
authors.lastname: Porter
authors.forename: B C
authors.initials: BC
authors.lastname: Ross
authors.forename: M
authors.initials: M
authors.lastname: Stephens-Smith
authors.forename: P
authors.initials: P
authors.lastname: Ward
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018039:Receptors, Tachykinin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007769:Lactams; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins