title: Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists.
abstract: A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human mu-opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant micro-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.
authors.affiliation: Department of Computational & Structural Sciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
authors.forename: F E
authors.initials: FE
authors.lastname: Blaney
authors.forename: L F
authors.initials: LF
authors.lastname: Raveglia
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: S
authors.initials: S
authors.lastname: Cavagnera
authors.forename: C
authors.initials: C
authors.lastname: Dartois
authors.forename: C
authors.initials: C
authors.lastname: Farina
authors.forename: M
authors.initials: M
authors.lastname: Grugni
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: M
authors.initials: M
authors.lastname: Martinelli
authors.forename: G M
authors.initials: GM
authors.lastname: Nadler
authors.forename: C
authors.initials: C
authors.lastname: Parini
authors.forename: P
authors.initials: P
authors.lastname: Petrillo
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
authors.forename: M A
authors.initials: MA
authors.lastname: Scheideler
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: G A
authors.initials: GA
authors.lastname: Giardina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009025:Morpholines; D010880:Piperidines; D011804:Quinolines; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D017450:Receptors, Opioid, mu; C427730:SB 400238; C427731:SB 414240