Synthesis of 2-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo [3.2.1]octanes and 2 alpha-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-enes as potential muscarinic agonists.
Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [3H]QNB and [3H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10(-6) and 1.79 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10(-4) M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo- [3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.
Triggle
D J
DJ
Department of Biochemical Pharmacology, School of Pharmacy, State University of New York, Buffalo 14260.
Kwon
Y W
YW
Abraham
P
P
Rahman
M A
MA
Carroll
F I
FI
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D009206:Myocardium / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014162:Transfection
D001643:Bridged Bicyclo Compounds; D010069:Oxadiazoles; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic