Synthesis of thiadiazole based carbamates as potent endocannabinoid-hydrolyzing enzyme inhibitors
Year: 2013
Type: dissertation
Abstract: Endocannabinoids are natural bioactive lipids which cause activation of cannabinoid receptors CB1 and CB2; and play an important role in numerous physiological and pathological conditions.However, endogenous lipids are rapidly hydrolyzed by fatty acid amide hydrolase (FAAH) and the monoacylglyceride lipase (MGL), the so called endocannabinoid degrading enzymes.Hence, the beneficial effects related to activation of cannabinoid receptors by endocannabinoids remains shorter.One potential approach to maintain levels of endocannabinoids is to block the endocannabinoid degrading enzymes by means of developing FAAH and/or MGL inhibitors.By means of mutagenesis and X-ray structures, it is well established that both FAAH and MGL contain serine residue (for FAAH: Ser 241 -Ser 217 -Lys 142 while for MGL: Ser 122 -Asp 239 -His 269 ) in their active sites.Thus, both enzymes belong to the serine hydrolase family.Hence, the earlier development related to FAAH and MGL inhibitors were focused on more activated substrates analogues and via modification of known serine hydrolase inhibitors.At present, a growing number of potent inhibitors have been developed in recent years; some selective to either of the enzymes and others exhibiting dual inhibition.3,4disubstituted 1,2,5-thiadiazole carbamates have been shown in recent studies to be potent and selective inhibitors of lysosomal acid lipase (LAL), the enzyme responsible for the Niemann-Pick type C disease (NPC).Since both FAAH and MGL belong to the same serine hydrolase superfamily as LAL and have same kind of mechanism of inhibition, we thought to screen these analogues against both FAAH and MGL.In this study, we developed several 3,4-disubstituted 1,2,5-thiadiazole based carbamates and other analogues such as esters and sulfonate.Several of these analogues were synthesized as per the literature procedure.In vitro studies were carried out to determine
Author: Yahaya Adams
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2185857757