2-Methyl-1,3-dioxaazaspiro[4.5]decanes as novel muscarinic cholinergic agonists.
Many nonquaternary ammonium muscarinic agonists have been developed over the last few years, but most of the existing compounds (e.g., arecoline, RS-86, AF-30) behave as weak partial agonists at cholinergic receptors in tissues of limited receptor reserve. The current paper describes the synthesis and biochemical assessment of analogues of AF-30 designed to have sufficient conformational freedom to allow greater receptor flexibility and hence activation. The new compounds and important standards were tested in a new biochemical assay designed to measure both receptor affinity and intrinsic activity of each compound and for their ability to stimulate phosphatidylinositol turnover in rat cerebral cortex. Two azaspirodecanes (5a and 5b) were shown to have far greater predicted efficacy than AF-30.
Saunders
J
J
Chemistry Department, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
Showell
G A
GA
Snow
R J
RJ
Baker
R
R
Harley
E A
EA
Freedman
S B
SB
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004148:Dioxolanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000378:metabolism; D013141:Spiro Compounds; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D004148:Dioxolanes; D004149:Dioxoles; D007295:Inositol Phosphates; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D013141:Spiro Compounds; C052394:2'-methylspiro-(1-azabicyclo(2.2.2.)octane-3,4'-(1,3)-dioxolane); D010095:Oxotremorine; D019832:N-Methylscopolamine