Synthesis and muscarinic activities of 1,2,4-thiadiazoles.
A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.
MacLeod
A M
AM
Chemistry Department, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
Baker
R
R
Freedman
S B
SB
Patel
S
S
Merchant
K J
KJ
Roe
M
M
Saunders
J
J
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014961:X-Ray Diffraction
D007202:Indicators and Reagents; D008024:Ligands; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D013830:Thiadiazoles; D010095:Oxotremorine; D019832:N-Methylscopolamine