Synthesis and Pharmacological Evaluation of M4 Muscarinic Receptor Positive Allosteric Modulators Derived from VU10004

被引：14
作者：
Huynh, Tracey [1 ]
Valant, Celine [2 ]
Crosby, Ian T. [1 ]
Sexton, Patrick M. [2 ]
Christopoulos, Arthur [2 ]
Capuano, Ben [1 ]
机构：
[1] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia
[2] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia
来源：
ACS CHEMICAL NEUROSCIENCE | 2015年 / 6卷 / 06期
基金：
英国医学研究理事会;
关键词：
Positive allosteric modulators; PAMs; muscarinic M-4 receptor; LY2033298; VU10004; BINDING;
D O I：
10.1021/acschemneuro.5b00035
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The M-4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M-4 PAMs derived from VU10004. These compounds investigate the pharmacological effects of target thieno[2,3-b]pyridines assembled from primary cycloalkanamines and cyclic secondary amines providing useful estimates of affinity (K-B), cooperativity (alpha beta), and direct agonist properties (tau(B)).
引用
收藏
页码：838 / 844
页数：7
相关论文
共 17 条
  • [1] Biel J. H., 1968, U.S. Patent, Patent No. [3,365,458, 3365458]
  • [2] Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats
    Brady, Ashley E.
    Jones, Carrie K.
    Bridges, Thomas M.
    Kennedy, J. Phillip
    Thompson, Analisa D.
    Heiman, Justin U.
    Breininger, Micah L.
    Gentry, Patrick R.
    Yin, Huiyong
    Jadhav, Satyawan B.
    Shirey, Jana K.
    Conn, P. Jeffrey
    Lindsley, Craig W.
    [J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 327 (03) : 941 - 953
  • [3] Bymaster FP, 1997, DRUG DEVELOP RES, V40, P158, DOI 10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.3.CO
  • [4] 2-6
  • [5] A Monod-Wyman-Changeux Mechanism Can Explain G Protein-coupled Receptor (GPCR) Allosteric Modulation
    Canals, Meritxell
    Lane, J. Robert
    Wen, Adriel
    Scammells, Peter J.
    Sexton, Patrick M.
    Christopoulos, Arthur
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (01) : 650 - 659
  • [6] Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia
    Chan, W. Y.
    McKinzie, D. L.
    Bose, S.
    Mitchell, S. N.
    Witkin, J. M.
    Thompson, R. C.
    Christopoulos, A.
    Lazareno, S.
    Birdsall, N. J. M.
    Bymaster, F. P.
    Felder, C. C.
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (31) : 10978 - 10983
  • [7] Ellis J, 1997, DRUG DEVELOP RES, V40, P193
  • [8] 4,6-Dimethyl-2-thioxo-1,2-dihydropyridine3-carbonitrile
    Eyduran, Fatih
    Oezyuerek, Cengiz
    Dilek, Nefise
    Iskeleli, Nazan Ocak
    Sendil, Kivilcim
    [J]. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2007, 63 : O2415 - O2417
  • [9] Selective Synthesis of Isoquinolin-3-one Derivatives Combining Pd-Catalysed Aromatic Alkylation/Vinylation with Addition Reactions: The Beneficial Effect of Water
    Ferraccioli, Raffaella
    Forni, Alessandra
    [J]. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2009, 2009 (19) : 3161 - 3166
  • [10] Hamaoka S., 2006, U.S. Patent Appl. Publ, Patent No. 20060116364
12