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Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carbamate compounds were developed to inhibit almost all members of the serine hydrolase family via covalent modification of serine at the active site (Kathuria et al., 2003; Long et al., 2009; Chang et al., 2013). Carbamates have been identified as potent inhibitors of AchE and these compounds have been widely used for the pest control in several crops, as well as in poultry and domestic animals (Roy et al., 2012; Casida and Durkin, 2013). Recently, several cholinesterase inhibitors containing the carbamate moiety, such as JZL184 and phenethylcymserine, were found to be CES inhibitors (Table 9.11) (Crow et al., 2012; Tsurkan et al., 2013). But all these compounds displayed poor isoform selectivity towards mammalian CES. Strong inhibition of carbamates on CES could be attributed to the very slow hydrolysis rates of the carbamoyl-enzyme intermediate, which was much slower than that of the acetyl-enzyme intermediate (Fig. 9.7) (Scaloni et al., 1994).
Endocannabinoids and addiction memory: Relevance to methamphetamine/morphine abuse
Published in The World Journal of Biological Psychiatry, 2022
Mirmohammadali Mirramezani Alizamini, Yonghui Li, Jian-Jun Zhang, Jing Liang, Abbas Haghparast
BLA also sends glutamatergic projections to the mPFC, which this neurotransmission modulates the consolidation of the memory (Yu et al. 2012). Sharifi et al. reported a functional interaction between the basolateral amygdala (BLA) ECS and the VTA glutamatergic neurotransmission in the modulation of morphine-induced passive avoidance memory consolidation impairment (Sharifi et al. 2017). In this regard, Sharifi et al. observed that the response of an ineffective dose of morphine was potentiated by activation of the CB1R through arachydonilcyclopropylamide, a cannabinoid CB1R agonist, and led to a memory disruption. Alteration of the glutamate can theoretically be controlled as it was revealed that 2-AG in association with JZL184 (inhibitor of the enzyme monoacylglycerol lipase) reduced the glutamatergic activity from BLA to the NAc (Folkes 2020).
Targeting the endocannabinoid system as a potential anticancer approach
Published in Drug Metabolism Reviews, 2018
Rico Schwarz, Robert Ramer, Burkhard Hinz
The major enzyme of 2-AG turnover, MAGL, poses another attractive target of anticancer strategies. Accordingly, the MAGL inhibitor JZL184 and MAGL knockdown were demonstrated to confer antiproliferative and proapoptotic effects on colorectal cancer cells in vitro and in vivo (Ye et al. 2011). MAGL knockdown and treatment with JZL184 were further found to confer an inhibitory action on prostate carcinoma cell invasion as well as on the growth of prostate carcinoma xenografts in vivo (Nomura et al. 2011). Concerning the underlying mechanism, the latter investigation reported a partial contribution of the CB1 receptor to the anti-invasive and growth inhibitory impact of MAGL inhibition. In addition to this cannabinoid action, add-back of MAGL products such as free fatty acid conferred a partial inhibition of the anti-invasive effect of MAGL inhibition. These findings support the hypothesis that MAGL activity provides procancerogenic lipid precursors for synthesis of lysophosphatidic acid and PGs which could be confirmed using diverse cancer cell lines (Nomura et al. 2010). Notably, the latter study could not find CB1 and CB2 receptor antagonists to rescue the migratory defects of MAGL knockdown cells, suggesting that the impact of MAGL on cancer aggressiveness did not involve endocannabinoid signaling.
Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation
Published in Expert Opinion on Drug Discovery, 2020
The strongest evidence that modulation of 2-AG may impact nicotine withdrawal comes from cross-species work using a range of molecular, genetic and pharmacological techniques [121]. This 2015 report contains data from mouse and human studies and finds that in mice: basal MAGL mRNA expression correlates with nicotine withdrawal signs, genetic knock-out of MAGL attenuates nicotine withdrawal, and inhibition of MAGL with JZL184 reduces somatic and aversive nicotine withdrawal signs. These effects of MAGL inhibition were blocked by rimonabant providing evidence for a CB1 receptor mediated mechanism. Further, human evidence is presented demonstrating an association between genetic variation within the MAGL gene and smoking withdrawal. In another study, MAGL inhibition with JZL184 had no effect on cognitive deficits associated with nicotine abstinence in mice. However, inhibition of the biosynthesis of 2-AG with O7460 prevented such deficits [109]. MAGL inhibitors have anxiolytic properties [115,122] but this has not been examined in relation to nicotine and abstinence-induced anxiety. Together these findings are consistent with the theory that increasing 2-AG levels may reduce withdrawal signs. Therefore, further work examining the impact of 2-AG modulation on nicotine withdrawal is warranted. This work should consider potential adverse effects of ligands used. For instance, it has been suggested that MAGL inhibition may be associated with impaired motor activity and cannabimimetic side effects whereas this is not the case with FAAH inhibition [122,123]. Dual FAAH/MAGL inhibitors such as SA-57, which is 100-fold more potent at inhibiting FAAH than MAGL, have also been developed. SA-57 appears to have efficacy at reducing withdrawal effects in morphine-dependent mice [123] but research in nicotine dependent animals is lacking.