Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)
Introduction
New psychoactive substances are constantly emerging on the illicit drug market and typically sold via the Internet. Of particular interest are N-2-methoxybenzyl-phenethylamines (NBOMe drugs), which are novel and reportedly very potent hallucinogens that have been increasingly used recreationally (Forrester, 2014, Hill et al., 2013, Ninnemann and Stuart, 2013, Rose et al., 2013, Walterscheid et al., 2014, Wood et al., 2015, Zuba, 2012), with additional potential use as radiotracers (Ettrup et al., 2011, Ettrup et al., 2010). Recreationally used NBOMe drugs include 25I-NBOMe, 25C-NBOMe, 25B-NBOMe, and 25D-NBOMe (Armenian and Gerona, 2014, Poklis et al., 2014, Rose et al., 2013), which are derivatives of 2,5-dimethoxy-4-substituted phenethylamines (2C drugs; Dean et al., 2013, Hill and Thomas, 2011, Shulgin and Shulgin, 1991) (see Fig. 1). N-2-methoxybenzyl substitution enhances the potency of 2C drugs at serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors, resulting in exceptionally potent 5-HT2A receptor agonists (Braden et al., 2006, Heim, 2004, Nichols et al., 2015) with strong hallucinogenic properties in animals and humans (Halberstadt and Geyer, 2014, Srisuma et al., 2015). Pharmacological interactions between NBOMe drugs and 5-HT2 receptors have been well characterized for some compounds of this novel drug family (Blaazer et al., 2008, Braden et al., 2006, Ettrup et al., 2011, Ettrup et al., 2010, Hansen et al., 2014, Nichols et al., 2008). However, systematic characterizations of the effects of a larger series of NBOMe drugs at a wider range of relevant human receptors and comparisons with their 2C parent drugs are lacking. Importantly, NBOMe drugs have been reported to produce psycho- and cardiovascular stimulant effects, in addition to hallucinations. Specifically, sympathomimetic toxicity, including tachycardia, hypertension, mydriasis, agitation, and hyperthermia, is commonly reported in cases of acute NBOMe drug intoxication (Hill et al., 2013, Rose et al., 2013, Srisuma et al., 2015, Stellpflug et al., 2014, Wood et al., 2015). Pharmacologically, compounds of the 2C series, including 2C-C, 2C-E, and 2C-I, inhibit the norepinephrine (NE) and serotonin transporters (NET and SERT, respectively), similar to amphetamines, although with only very low potency (Eshleman et al., 2014, Nagai et al., 2007). These findings raise the question of whether NBOMe drugs may have similar but more potent stimulant-type pharmacological properties, including inhibition of the NET, dopamine (DA) transporter (DAT), and SERT, or interactions with adrenergic α1 receptors that lead to vasoconstriction.
We assessed the in vitro pharmacology of a series of NBOMe drugs compared with their 2C parent drugs. We characterized the binding affinity profiles at monoamine receptors and DAT, NET, and SERT inhibition potencies. We also determined the functional 5-HT2A receptor activation potencies because 5-HT2A receptors mediate hallucinogenic effects (Nichols, 2004). The prototypical serotonergic hallucinogen lysergic acid diethylamide (LSD) was included as a comparator drug (Nichols, 2004, Passie et al., 2008).
Section snippets
Drugs
2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, mescaline, 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOMe, 25N-NBOMe, 25P-NBOMe, 25T2-NBOMe, 25T4-NBOMe, 25T7-NBOMe, and mescaline-NBOMe were synthesized by Lipomed (Arlesheim, Switzerland) for this study at no cost. All of the compounds were used as hydrochloride salts. Purity was >98% for all of the substances. [3H]NE and [3H]DA were obtained from Perkin–Elmer (Schwerzenbach, Switzerland), and [3H]5-HT
Interactions with serotonin receptors
Table 1 shows binding to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, activation potency and efficacy at 5-HT2A and 5-HT2B receptors, and 5-HT receptor binding ratios. All of the compounds exhibited high binding affinity for 5-HT2A and 5-HT2C receptors (Ki < 1 μM, with the exception of 2C-H and mescaline). N-2-methoxybenzyl substitution further increased the average binding affinity for both 5-HT2A and 5-HT2C receptors 26- and 14-fold (range: 6–100 and 8–32, respectively), leading to
Discussion
We pharmacologically characterized the in vitro receptor interaction profiles of novel recreationally abused hallucinogenic N-2-methoxybenzyl-substituted phenethylamines compared with their 2C phenethylamine analogs. Both the NBOMe and 2C drugs potently interacted with serotonin 5-HT2A, 5-HT2B, 5-HT2C receptors and TAAR1rat. We also found several consistent and potentially important structure-affinity relationships for the NBOMe drugs, their 2C analogs, and several targets. Specifically, N
Conflicts of interest
M.C.H. is an employee of F. Hoffmann-La Roche.
Authorship contributions
Participated in research design: Rickli, Liechti.
Conducted experiments: Rickli, Luethi, Reinisch, Buchy.
Performed data analysis: Rickli, Hoener, Liechti.
Wrote or contributed to the writing of the manuscript: Rickli, Liechti.
Acknowledgments
This work was supported by the Federal Office of Public Health (no. 13.006497) and Translational Medicine Hub Innovation Fund of F. Hoffmann-LaRoche and the University of Basel. The authors thank Sylvie Chaboz for technical assistance, Lipomed (Arlesheim, Switzerland) for providing the 2C and NBOMe drugs at no cost, and Michael Arends for text editing.
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