A novel class of conformationally restricted heterocyclic muscarinic agonists.
A series of conformationally restricted compounds containing the 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) skeleton, including O-methyl-THPO (10a) and O,5-dimethyl-THPO (11a), were synthesized. The compounds were designed by bioisosteric replacement of the methyl ester groups of the muscarinic cholinergic agonists norarecoline and arecoline by the 3-methoxyisoxazole group, and their interactions with central and peripheral muscarinic receptors were tested in vitro. The compounds 10a, 11a, O-ethyl-THPO (10b), O-propargyl-THPO (10j), and O-ethyl-5-methyl-THPO (11b) were inhibitors of the binding of the muscarinic mustard [3H]PrBCM to rat brain membranes with an increasing order of potency. There was, however, a very low degree of correlation between these binding data and the effects of the compounds on peripheral (ileal) muscarinic receptors, where 11a, 10j, 11b, and 10a were agonists with a decreasing order of potency, whereas O-isopropyl-THPO (10e) showed antagonistic effects. The relatively low pKa values of the compounds (7.5-7.7 for compounds with secondary and 6.1-7.0 for compounds with tertiary amino groups) are likely to allow the compounds to penetrate the blood-brain barrier.
P
P
Sauerberg
J J
JJ
Larsen
E
E
Falch
P
P
Krogsgaard-Larsen
D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008968:Molecular Conformation; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D011438:Propylbenzilylcholine Mustard / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D014316:Tritium; D011438:Propylbenzilylcholine Mustard