A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1-methylpyridines (substituted-TZTP; 5a-l, 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 C1-8 alkoxy-TZTP 5a-l 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 C1-8 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 C3-8 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-tetrahy dro-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 C5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M1 selective muscarinic agonists.
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http://dx.doi.org/10.1021/jm00090a019 | DOI Listing |
BMC Urol
December 2024
Department of Urology, 920th Hospital of Joint Logistic Support Force, Kunming, 650000, China.
Background: To analyze the safety and efficacy of microsurgical subinguinal varicocelectomy(MSV) performed with and without preservation of all testicular arteries and lymphatic system.
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BMC Urol
December 2024
Department of Andrology, the Center for Men's Health, Shanghai General Hospital, Urologic Medical Center, Shanghai Jiao Tong University, Shanghai, 200080, China.
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View Article and Find Full Text PDFInt J Mol Sci
December 2024
Department of Biomedical Science, College of Life Science, CHA University, Pocheon 11160, Gyeonggi-do, Republic of Korea.
Idiopathic male infertility is characterized by increased mortality or reduced motility and vitality of sperm. There are several reports on probiotics in the male reproductive tract, but the effects of these probiotics on sperm motility remain to be elucidated. In this study, we investigated the impact and mechanism of probiotics on the vitality and motility of mouse sperm.
View Article and Find Full Text PDFAndrology
December 2024
Centre d'épidémiologie et de recherche en santé des populations (CERPOP), Université Toulouse III Paul-Sabatier, Toulouse, France.
Congenital absence of the vas deferens (CAVD) is a syndrome with a heterogeneous presentation: bilateral (CBAVD) or unilateral (CUAVD), complete or partial and associated or not with other anomalies of the male urogenital system. A turning point came in 1968 when CBAVD was associated with cystic fibrosis and its CFTR gene mutations. Genetic studies then revealed that a minority of CBAVD but a majority of CUAVD are CFTR-independent.
View Article and Find Full Text PDFBMC Urol
December 2024
Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Background: Zinner syndrome (ZS) is a congenital malformation characterized by a triad of mesonephric (Wolffian) duct dysplasia, first identified by Zinner in 1914. The classical presentation of ZS includes unilateral renal hypoplasia or dysplasia, ipsilateral seminal vesicle cysts, and obstruction of the ejaculatory duct. This case presents a rare variant of the syndrome, where an ejaculatory duct cyst is observed instead of the typical ipsilateral seminal vesicle cyst.
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