Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6- tetrahydro-1-methylpyridines

Article abstract of DOI:10.1021/jm00090a019

A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6- tetrahydro-1-methylpyridines (substituted-TZTP; 5a-1, 7a-h, 8, 9c-n, 11, 13j) were synthesized and tested for central muscarinic cholinergic receptor affinity by using [³H]-oxotremorine-M (Oxo-M) and [³H]-pirenzepine (Pz) as ligands. The potency and efficacy of the compounds for the pharmacological defined M₁ and M₂ muscarinic receptors were determined on isolated electrically stimulated rabbit vas deferens and on spontaneously beating isolated guinea pig atria, respectively. Selected compounds were also tested for M₃ activity in the isolated guinea pig ileum. The C_1-8 alkoxy-TZTP 5a-1 analogues all displaced [³H]-Oxo-M and [³H]-Pz with low nanomolar affinity. Depicting chain length against Oxo-M binding and against Pz binding the unbranched C_1-8 alkoxy-TZTP (5a-h) derivatives produced U-shaped curves with butoxy- (5d) and (pentyloxy)-TZTP (5e) as the optimum chain length, respectively. This U-shaped curve was also seen in the ability of the compounds 5a-h to inhibit the twitch height in the vas deferens preparation. The (pentyloxy)- (5e) and the (hexyloxy)-TZTP (5f) analogues produced an over 90% inhibition of the twitch height with IC₅₀ values in the low picomolar range. In both the atria and in the ileum preparations 5f had low efficacy and potency. With the (alkylthio)-TZTP (7a-h) analogues the structure- activity relationship was similar to the one observed with the alkoxy (5a-h) analogues, but generally 7a-h had higher receptor affinity and was more potent than the corresponding 5a-h. However, the C_3-8 alkyl-TZTP (9c,e,g,h) analogues had 10-100 times lower affinity for the central muscarinic receptors than the corresponding alkoxy and alkylthio derivatives, and their efficacy in the vas deferens preparation was too low to obtain IC₅₀ values. The unsubstituted TZTP (11) compound was a potent but nonselective muscarinic agonist. The two 3-(3-butoxy/(hexyloxy)-1,2,5- oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridines (butoxy/(hexyloxy)-OZTP; 19a/b) were also synthesized and tested. Both 19a and 19b had much lower affinity for the central muscarinic receptors than 5d and 5f, and the efficacy of 19a,b was too low to give IC₅₀ values in the vas deferens preparation. Therefore, the C_5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M₁ selective muscarinic agonists.