Please cite this article in press as: Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res (2014), http://dx. doi. org/10. 1016/j. bbr. 2014. 07. 016ARTICLE IN PRESSG Model BBR 9035 1-22 2 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx Fig. 1. Chemical structures of indolealkylamine, phenylalkylamine, and ergoline hallucinogens. and the chemically simpler indolealkylamines, which includes N,N-dimethyltryptamine (DMT), N,N-dipropyltryptamine (DPT), 5-methoxy-DMT (5-Me O-DMT), and psilocybin (4-phosphoryloxy-DMT) and its active O-dephosphorylated metabolite psilocin (4-hydroxy-DMT). DMT is found in several hallucinogenic snuffs used in the Caribbean and in South America. It is also a com-ponent of ayahuasca, an infusion or decoction prepared from DMT-containing plants in combination with species of Banisteriop-sis containing /H9252-carboline alkaloids that act as monoamine oxidase inhibitors [7]. Psilocybin and its metabolite psilocin are the active components of hallucinogenic teonanácatl mushrooms belonging to the genus Psilocybe. The phenylalkylamines can be subdivided into phenethy-lamines, such as mescaline from the peyote cactus (Lophophora williamsii ), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I); and phenylisopropylamines (“amphetamines”), including DOM, 2,5-dimethoxy-4-iodoamphetamine (DOI), and 2,5-dimethoxy-4-bromoamphetamine (DOB). Although N-alkyl substituted phenylalkylamines are usually inactive as hallucinogens, the addition of a N-benzyl group to phenethylamines can dramat-ically increase their activity, and N-benzylphenethylamines are a new class of potent hallucinogenic compounds [8]. Examples of N-benzylphenethylamine hallucinogens include N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine(25I-NBOMe) and N-(2-methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (25B-NBOMe). The chemical structures of many of these hallucinogens are illustrated in Fig. 1. Nichols and colleagues have also developed conformationally restricted derivatives of phenylalkylamine hallucinogens: bromo-Dragon FLY (1-(8-bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-amino-propane; [9]); TCB-2 (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; [10]; and 2S,6S-DMBMPP ((2 S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine; [11]). Likewise, lysergic acid 2,4-dimethylazetidide was developed as a rigid analog of LSD that shows similar in vivo potency [12]. Fig. 2 shows examples of rigid hallucinogen analogs. Phenylalkylamine hallucinogens are selective for 5-HT 2recep-tors, including 5-HT 2A, 5-HT 2B, and 5-HT 2Csites [13-15]. The indolealkylamines, by contrast, bind non-selectively to 5-HT recep-tors. Certain indolealkylamines, most notably DMT and some of its derivatives, bind to /H92681receptors [16] and the trace amine receptor [17], and are substrates for the 5-HT trans-porter (SERT) [18,19]. However, compared with /H92681and SERT, tryptamines are more potent at 5-HT 1Aand 5-HT 2Areceptors by several orders of magnitude, so the former sites probably do not contribute to the hallucinogenic response. LSD and other ergoline hallucinogens display high afﬁnity for 5-HT receptors, as well as dopaminergic and adrenergic receptors (reviewed by: [6,20] ). 59 60616263646566676869707172737475767778798081828384 858687888990919293949596979899100101102103104105106107108