Alzheimer’s disease is a neurodegenerative disease that impacts many individuals today. Previous agonists, like NNC 26-9100, have shown agonistic activity at the somatostatin subtype-4 receptor, leading to a decrease in neprilysin accumulation. Current research is directed at synthesizing and studying potential agonists targeting somatostatin subtype-4 receptors. Compounds containing a 1,2,4-triazole nucleus have been used as a scaffold for selective sst4 agonists. Research in the laboratory has been focused on further studying the SAR of trisubstituted-1,2,4-triazoles. This research describes the synthesis, characterization, and pharmacological evaluation of three 3-thio-1,2,4-triazoles. The results of this research have shown variation of the substitution of the 3-and 5-positions of the 1,2,3-triazole nucleus can dramatically affect affinity at the sst4.
Functional activity of the 3-thio-1,2,4-triazoles was assessed in an assay based on inhibition of forskolin-stimulated of cAMP production in recombinant Chinese hamster ovary (CHO-KI) cells that expressed sst4. Optimal binding was seen in the 3-indolylmethyl group series when the benzyl group was substituted in the meta-position 35. A decrease in affinity for sst4 was observed when the 3-thio-1,2,4-triazoles were substituted with a 2-phenylethyl group at position 5, (16 and 17), when compared with phenylmethyl derivatives. When a 3-methoxy benzyl group was incorporated at position 3 of the 3-thio-1,2,4-triazole, in the 2-phenylmethyl series (17), a slight increase in binding affinity was observed. Large substituents, in the para-position, of the benzyl group at position 3 are not well tolerated in comparison to substitution in the meta-position in 3-thio-1,2,4-triazoles compounds containing a 3-indolylmethyl group at position-5 (compounds 10 and 11). With data collected, SAR gaps can be filled in to better understand agonistic activity at sst4.
|Advisor:||Crider, A. Michael|
|Commitee:||Witt, Ken, Nieto, Marcelo|
|School:||Southern Illinois University at Edwardsville|
|School Location:||United States -- Illinois|
|Source:||MAI 81/3(E), Masters Abstracts International|
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