3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-α]phthalazines and analogues:: High-affinity γ-aminobutyric acid-A benzodiazepine receptor ligands with α2, α3, and α5-subtype binding selectivity over α1

被引:151
作者
Carling, RW
Moore, KW
Street, LJ
Wild, D
Isted, C
Leeson, PD
Thomas, S
O'Connor, D
McKernan, RM
Quirk, K
Cook, SM
Atack, JR
Wafford, KA
Thompson, SA
Dawson, GR
Ferris, P
Castro, JL
机构
[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Med Chem, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Biochem, Harlow CM20 2QR, Essex, England
[3] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Pharmacol, Harlow CM20 2QR, Essex, England
关键词
D O I
10.1021/jm031020p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha3- and alpha5-containing receptor subtypes over the GABA-A alpha1 subtype (K-i: alpha2 = 850 nM, alpha3 = 170 nM, alpha5 = 72 nM, alpha1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: alpha2 = 16 nM, alpha3 = 41 nM, alpha5 = 38 nM, alpha1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K-i: alpha2 = 1.7 nM, alpha3 = 0.71 nM, alpha5 = 0.33 nM, alpha1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha1, -7%; alpha2, -5%; alpha3, -16%; alpha5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha3 over alpha1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of I h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha2/alpha3 agonist in vivo.
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页码:1807 / 1822
页数:16
相关论文
共 40 条
  • [11] AMNESIC EFFECT OF DIAZEPAM (VALIUM)
    CLARKE, PRF
    ECCERSLEY, PS
    FRISBY, JP
    THORNTON, JA
    [J]. BRITISH JOURNAL OF ANAESTHESIA, 1970, 42 (08) : 690 - +
  • [12] 3-heteroaryl-2-pyridones:: Benzodiazepine site ligands with functional selectivity for α2/α3-subtypes of human GABAA receptor-ion channels
    Collins, I
    Moyes, C
    Davey, WB
    Rowley, M
    Bromidge, FA
    Quirk, K
    Atack, JR
    McKernan, RM
    Thompson, SA
    Wafford, K
    Dawson, GR
    Pike, A
    Sohal, B
    Tsou, NN
    Ball, RG
    Castro, JL
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (09) : 1887 - 1900
  • [13] TRICYCLIC HETEROAROMATIC SYSTEMS - [1]BENZOPYRANOPYRROL-4-ONES AND [1]BENZOPYRANO-1,2,3-TRIAZOL-4-ONES AS BENZODIAZEPINE RECEPTOR LIGANDS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS
    COLOTTA, V
    CECCHI, L
    MELANI, F
    FILACCHIONI, G
    MARTINI, C
    GIANNACCINI, G
    LUCACCHINI, A
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (09) : 2646 - 2651
  • [14] Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit
    Davies, PA
    Hanna, MC
    Hales, TG
    Kirkness, EF
    [J]. NATURE, 1997, 385 (6619) : 820 - 823
  • [15] Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer
    Farrar, SJ
    Whiting, PJ
    Bonnert, TP
    McKernan, RM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (15) : 10100 - 10104
  • [16] GRUNDSTROM R, 1978, ACTA PHARMACOL TOX, V43, P13
  • [17] HADINGHAM KL, 1993, MOL PHARMACOL, V43, P970
  • [18] STRUCTURAL REQUIREMENTS FOR AGONIST ACTIONS AT THE BENZODIAZEPINE RECEPTOR - STUDIES WITH ANALOGS OF 6-(BENZYLOXY)-4-(METHOXYMETHYL)-BETA-CARBOLINE-3-CARBOXYLIC ACID ETHYL-ESTER
    HOLLINSHEAD, SP
    TRUDELL, ML
    SKOLNICK, P
    COOK, JM
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (03) : 1062 - 1069
  • [19] Huang Q, 1999, Drug Des Discov, V16, P55
  • [20] CENTRAL MUSCLE RELAXANT EFFECTS OF DIAZEPAM
    HUDSON, RD
    WOLPERT, MK
    [J]. NEUROPHARMACOLOGY, 1970, 9 (05) : 481 - &