Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class

Abstract

R., Maurer, Hans H., Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class.Toxicology Letters http://dx.doi.org/10.1016/j.toxlet. 2015.11.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.  IC50 values were comparable to that of clinically relevant inhibitors. Members of the DALT family were strong inhibitors of CYP1A2 and CYP2D6 activity. 5-MeO-DALT showed in vivo inhibition against CYP1A2 activity. ABSTRACTNew psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100 µM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further.

Analytical characterization of N,N‐diallyltryptamine (DALT) and 16 ring‐substituted derivatives

“…In recent years, 5‐MeO‐DALT ( 7 ) has been frequently discussed within the context of being a new psychoactive substance (NPS) where many of these substances are advertised as ‘research chemicals’ and available for purchase from Internet retailers or shops . As far as the availability of analytical data are concerned, the majority of available reports describing the detection and characterization of DALT derivatives focus on 5‐MeO‐DALT ( 7 ), reflecting its appearance in forensically related casework and/or from retail purchases (Table ).…”

“…The present study provided a comprehensive set of spectral data obtained from 17 N , N ‐diallyltryptamines in order to facilitate the identification and exploration of these newly emerging substances. Another challenge frequently encountered with new psychoactive substances is the lack of information regarding their biological properties, which triggered a first set of studies carried out in the authors’ laboratories in the areas of metabolism and cytochrome P450 inhibition . Receptor binding data for 5‐MeO‐DALT ( 7 ) and additional DALTs substituted at the 5‐position have also appeared recently .…”

“…Another challenge frequently encountered with new psychoactive substances is the lack of information regarding their biological properties, which triggered a first set of studies carried out in the authors' laboratories in the areas of metabolism [59] and cytochrome P450 inhibition. [61] Receptor binding data for 5-MeO-DALT (7) [45] and additional DALTs substituted at the 5position have also appeared recently. [63] The fact that a range of closely related N,N-dialkylated tryptamines (e.g.…”

“…Furthermore, the psychoactive properties associated with a range of N,Ndialkylated tryptamines make the DALT compounds a desirable target for pharmacological and pharmacokinetic investigations as reported recently for some of the compounds characterized in the present study. [59,[61][62][63] In addition to 5-MeO-DALT (7), [30] the two additional DALT analogues 4-AcO-DALT (3) [64] and DALT (1), [65] also described here in the present study, have been detected by the European Early-Warning System and reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCCDA), which suggested that the development of new DALT analogues might be a likely prospect within the 'research chemicals' context.…”

3-Fluorophenmetrazine, a fluorinated analogue of phenmetrazine: Studies on in vivo metabolism in rat and human, in vitro metabolism in human CYP isoenzymes and microbial biotransformation in Pseudomonas Putida and wastewater using GC and LC coupled to (HR)-MS techniques

“…Phenmetrazine metabolites were assumed to arise from phenmetrazine metabolism and not dehalogenated 3-FPM metabolites, however, as we did not have an analytical standard for 3-FPM this assumption remains untested. The large relative amount of phenmetrazine in the human samples could change the profile of absorption, distribution, metabolism and excretion for instance by inhibition [22][23][24]. The main MBPs of 3-FPM in wastewater were the carboxy metabolite (8), while in P. putida TSB growth cultures it was the N-oxide (1).…”