title: Conformationally constrained analogues of the muscarinic agonist 3-(4-(methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyr idine. Synthesis, receptor affinity, and antinociceptive activity.
abstract: Conformationally constrained analogues of the potent muscarinic agonist 3-(4-methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methy lpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the antinociceptive selectivity over salivation and tremor and (b) predicting the active conformation of 17 with respect to the dihedral angle C4-C3-C3'-N2'. Using MOPAC 6.0 tricyclic analogues (7, 15, 16) with C4-C3-C3'-N2' dihedral angles close to 180 degrees and a rotation hindered analogue (9) with a C4-C3-C3'-N2' dihedral angle close to 274 degrees were designed, as these conformations had previously been suggested as being the active conformations. The analogues were tested for central muscarinic receptor binding affinity, for their antinociceptive activity in the mouse grid shock test, and, in the same assay, for their ability to induce tremor and salivation. The data showed that the tricyclic analogues (7, 15, 16) were equipotent with 17 as analgesics, but with no improved side effect profiles. The rotation-hindered analogue 9 had neither muscarinic receptor binding affinity nor antinociceptive activity. These results suggest that the active conformation of 17 has a C3-C4-C3'-N2' dihedral angle close to 180 degrees.
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: K
authors.initials: K
authors.lastname: Rimvall
authors.forename: H
authors.initials: H
authors.lastname: Thøgersen
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: B D
authors.initials: BD
authors.lastname: Sawyer
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: N W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004597:Electroshock; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010095:Oxotremorine / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000700:Analgesics; D018721:Muscarinic Agonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D010095:Oxotremorine