title: Tetrahydropyridyloxadiazoles: semirigid muscarinic ligands.
abstract: Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.
authors.affiliation: Chemistry Department Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
authors.forename: G A
authors.initials: GA
authors.lastname: Showell
authors.forename: T L
authors.initials: TL
authors.lastname: Gibbons
authors.forename: C O
authors.initials: CO
authors.lastname: Kneen
authors.forename: A M
authors.initials: AM
authors.lastname: MacLeod
authors.forename: K
authors.initials: K
authors.lastname: Merchant
authors.forename: J
authors.initials: J
authors.lastname: Saunders
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Baker
mesh_terms: D000818:Animals; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D003460:Crystallization; D006860:Hydrogen Bonding; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D010069:Oxadiazoles; D010277:Parasympathomimetics; D011725:Pyridines; D011976:Receptors, Muscarinic