Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline.
A series of O- and ring-alkylated derivatives of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol was synthesized via treatment of appropriately substituted 4-benzylamino-1,2,5,6-tetrahydropyridine-3-carboxamides with hydrogen sulfide and subsequent ring closure by oxidation with bromine. The muscarinic receptor affinity as well as estimated relative efficacy and subtype selectivity of this series of bicyclic arecoline bioisosteres were determined using rat brain membranes and a number of tritiated muscarinic receptor ligands. The effects at the five cloned human muscarinic receptor subtypes of a selected series of chiral analogues, with established absolute stereochemistry, were studied using receptor selection and amplification technology (R-SAT). The potency, relative efficacy, and receptor subtype selectivity of these compounds were related to the structure of the O-substituents and the position and stereochemical orientation of the piperidine ring methyl substituents.
Medicinal Chemistry Research, H. Lundbeck A/S, Valby-Copenhagen, Denmark.
H
H
Pedersen
H
H
Bräuner-Osborne
R G
RG
Ball
K
K
Frydenvang
E
E
Meier
K P
KP
Bøgesø
P
P
Krogsgaard-Larsen
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis*; D051381:Rats; D011976:Receptors, Muscarinic / Q000737:chemistry*
D011725:Pyridines; D011976:Receptors, Muscarinic; D001115:Arecoline; D002217:Carbachol