Conformational aspects of the muscarinic receptor interactions of bicyclic isoxazole ester bioisosteres of arecoline.
3-Methoxy-4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridine (O-Me-THPO) and O,5-di-Me-THPO are conformationally restricted bioisosteres of the muscarinic agonists norarecoline and arecoline, respectively, showing partial agonist effects at muscarinic acetylcholine receptors. The 7-membered ring analogue of O-Me-THPO, 3-methoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine (O-Me-THAO), shows higher affinity for muscarinic receptor sites than O-Me-THPO or O,5-di-Me-THPO. Similarly, O-Et-THAO binds much more tightly to muscarinic receptor sites than its 6-membered ring analogues, O-Et-THPO and O-Et-5-Me-THPO. Based on receptor binding data, O-Me-THPO and O-Me-THAO, and O-Et-THPO and O-Et-THAO, respectively, show similar degrees of partial agonism. They also show similar relative affinities for muscarinic M1 and M2 receptor sites. Using the semiempirical quantum mechanics programme, AM1, and the molecular mechanics programme, SYBYL, we have studied the conformational flexibility of the O-alkyl-THPO and O-alkyl-THAO ring systems. As expected, the 7-membered ring of the latter system was shown to be markedly more flexible than the piperidine rings of O-alkyl-THPO analogues. On the basis of this analysis, a common pharmacophore for these two classes of compounds was constructed.
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
A
A
Lagersted
E
E
Falch
B
B
Ebert
P
P
Krogsgaard-Larsen
D001115:Arecoline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008968:Molecular Conformation; D010277:Parasympathomimetics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D007555:Isoxazoles; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D001115:Arecoline