SUBSTITUENT VARIATION IN AZABICYCLIC TRIAZOLE-BASED AND TETRAZOLE-BASED MUSCARINIC RECEPTOR LIGANDS

被引:83
作者
JENKINS, SM
WADSWORTH, HJ
BROMIDGE, S
ORLEK, BS
WYMAN, PA
RILEY, GJ
HAWKINS, J
机构
关键词
D O I
10.1021/jm00091a007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl-, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands ha, been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
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页码:2392 / 2406
页数:15
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共 34 条
[1]  
Bartlett P. D., 1939, J AM CHEM SOC, V61, P3184
[2]   THE INVENTION OF NEW RADICAL CHAIN REACTIONS .8. RADICAL CHEMISTRY OF THIOHYDROXAMIC ESTERS - A NEW METHOD FOR THE GENERATION OF CARBON RADICALS FROM CARBOXYLIC-ACIDS [J].
BARTON, DHR ;
CRICH, D ;
MOTHERWELL, WB .
TETRAHEDRON, 1985, 41 (19) :3901-3924
[3]   1.3-CYCLOADDITIONEN MIT TRIMETHYLSILYL-AZID - UBER ISOMERE N-ACETYL-1.2.3-TRIAZOLE [J].
BIRKOFER, L ;
WEGNER, P .
CHEMISCHE BERICHTE-RECUEIL, 1966, 99 (08) :2512-&
[4]   VARIATION OF MUSCARINIC ACTIVITIES OF OXOTREMORINE ANALOGS [J].
BROWN, F ;
CLARK, M ;
GRAVES, D ;
HADLEY, M ;
HATCHER, J ;
MCARTHUR, R ;
RILEY, G ;
SEMPLE, J .
DRUG DEVELOPMENT RESEARCH, 1988, 14 (3-4) :343-347
[5]  
COREY EJ, 1972, TETRAHEDRON LETT, V36, P3769
[6]   A SYNTHESIS OF 1-AZABICYCLO[2.2.1]HEPTANE-3-CARBOXYLIC ACID-ESTERS IN ENANTIOMERICALLY PURE FORM [J].
COTTRELL, IF ;
HANDS, D ;
KENNEDY, DJ ;
PAUL, KJ ;
WRIGHT, SHB ;
HOOGSTEEN, K .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1991, (05) :1091-1097
[7]   THE DEVELOPMENT AND USE OF QUANTUM-MECHANICAL MOLECULAR-MODELS .76. AM1 - A NEW GENERAL-PURPOSE QUANTUM-MECHANICAL MOLECULAR-MODEL [J].
DEWAR, MJS ;
ZOEBISCH, EG ;
HEALY, EF ;
STEWART, JJP .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (13) :3902-3909
[8]   SELF-CONSISTENT MOLECULAR-ORBITAL METHODS .9. EXTENDED GAUSSIAN-TYPE BASIS FOR MOLECULAR-ORBITAL STUDIES OF ORGANIC MOLECULES [J].
DITCHFIELD, R ;
HEHRE, WJ ;
POPLE, JA .
JOURNAL OF CHEMICAL PHYSICS, 1971, 54 (02) :724-+
[9]   A NOVEL SERIES OF NONQUATERNARY OXADIAZOLES ACTING AS FULL AGONISTS AT MUSCARINIC RECEPTORS [J].
FREEDMAN, SB ;
HARLEY, EA ;
PATEL, S ;
NEWBERRY, NR ;
GILBERT, MJ ;
MCKNIGHT, AT ;
TANG, JK ;
MAGUIRE, JJ ;
MUDUNKOTUWA, NT ;
BAKER, R ;
STREET, LJ ;
MACLEOD, AM ;
SAUNDERS, J ;
IVERSEN, LL .
BRITISH JOURNAL OF PHARMACOLOGY, 1990, 101 (03) :575-580
[10]  
FREIDRICH K, 1979, CHEM FUNCTIONAL GROU, P89