As concerns TRPV assays benzylic amides and benzylic reverse

As concerns TRPV1 assays, benzylic amides and benzylic reverse amides exhibited an overall superiority over their aryl counterparts and , and ureas and . A reversed trend was however observed with the 4-chlorostyryl and 4--butylphenyl moieties (compare compounds and ; , , and ; and ). The EC and IC values were, with the exception of , , ,, ,, , and , comparable and thus, only , , ,, , and behaved as ‘true’ antagonists, while and acted as weakly desensitizing agonists. The boronic functional group was fully compatible with a TRPV1 modulating action but not essential for it, as demonstrated by the comparison between compounds and ,, and and SB-366791, and the inactivity of compounds , ,, ,,,, , and . Thirteen of the compounds examined, that is, ,–, –, , ,, , targeted both FAAH and TRPV1 channel. In particular, four of them, that is, , , , acted as dual FAAH/TRPV1 blockers, the first three compounds comparing favorably in terms of potency with the other chemotypes so far presented by us. The ability of these compounds to inhibit FAAH and activate/desensitize or directly antagonize TRPV1, that is, to target simultaneously two distinct targets involved in nociception, qualify them as promising antinociceptive, antihyperalgesic, and antioedemic agents in chronic and inflammatory pain preclinical studies. Acknowledgement This research was supported by Sapienza Università di Roma (Grant No C26A14TLFT).
In their Article in , Deepak Cyril D'Souza and colleagues from Yale University describe the results from a randomised clinical trial of a fatty DCG IV amide hydrolase (FAAH) inhibitor in 70 men seeking treatment for cannabis dependence (according to DSM-IV criteria). Participants were randomly assigned to an oral FAAH Inhibitor (PF-04457845 [provided by Pfizer, Groton, VT, USA]; ; 4 mg per day) or matching placebo and underwent a period of initial abstinence from cannabis for about 1 week during an inpatient stay on a research unit; they were then were discharged to outpatient care for an additional 3-week treatment period on study medications. The primary outcomes were treatment-related differences in cannabis withdrawal symptoms during admission, and self-reported cannabis use by timeline follow-back methods, and urine THC-COOH concentrations at end of treatment. Other outcome measures included craving symptoms and sleep measures. The results of this study suggest positive effects of PF-04457845 versus placebo on cannabis use, withdrawal symptoms, and sleep, with medium-to-large effect sizes suggesting that these effects are clinically meaningful. PF-04457845 reduced cannabis withdrawal symptoms (difference in mean symptom score on first day of treatment 4·96 [95% CI 0·71–9·21], p=0·048), self-reported cannabis use at 4 weeks (difference in joints per day 0·88 [95% CI 0·29–1·46]; p<0·0003), and urinary THC-COOH concentrations (difference 392·37 ng/mL [95% CI 17·55–767·18]; p=0·009). FAAH is an important target within the endocannabinoid system in the brain, because it catalyses the breakdown of anandamide, the principal endocannabinoid involved in CNS neurotransmission. Findings from PET studies have shown that cannabis use downregulates FAAH function, suggesting that FAAH inhibition could restore endocannabinoid function in patients with cannabis use disorder. Therefore, D'Souza and colleagues' study is very important, because it provides evidence that FAAH inhibition could be a viable therapeutic strategy to treat problematic cannabis use. Overall, cannabis is used by about 3·8% of the world's population, with a prevalence of cannabis dependence of 258·3 per 100 000 people. Given the absence of approved pharmacological treatments for cannabis use disorder, and that its prevalence could rise in the era of legalised recreational cannabis use—present now in Portugal, Uruguay, Canada, and nine US states and the District of Columbia—these results should be most welcome to patients, their families, clinicians, and policymakers.