Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.
Wadsworth
H J
HJ
SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Harlow, Essex, U.K.
Jenkins
S M
SM
Orlek
B S
BS
Cassidy
F
F
Clark
M S
MS
Brown
F
F
Riley
G J
GJ
Graves
D
D
Hawkins
J
J
Naylor
C B
CB
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004563:Electrochemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010095:Oxotremorine / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D013777:Tetrazoles; D014230:Triazoles; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate