Structure-Activity Relationships of Phenylalkylamines as Agonist Ligands for 5-HT 2A Receptors

Swammerdam Institute for Life Sciences, Centre for NeuroScience, University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam.
ChemMedChem (Impact Factor: 2.97). 10/2008; 3(9):1299-309. DOI: 10.1002/cmdc.200800133
Source: PubMed


Agonist activation of central 5-HT(2A) receptors results in diverse effects, such as hallucinations and changes of consciousness. Recent findings indicate that activation of the 5-HT(2A) receptor also leads to interesting physiological responses, possibly holding therapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5-HT(2A) ligands with agonist profiles are primarily derived from phenylalkylamines, indolealkylamines, and certain piperazines. Of these, phenylalkylamines, most notably substituted phenylisopropylamines, are considered the most selective agonists for 5-HT(2) receptors. This review summarizes the structure-activity relationships (SAR) of phenylalkylamines as agonist ligands for 5-HT(2A) receptors. Selectivity is a central theme, as is selectivity for the 5-HT(2A) receptor and for its specific signaling pathways. SAR data from receptor affinity studies, functional assays, behavioral drug discrimination as well as human studies are discussed.

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    • "Accordingly, 5-HT 1A receptor stimulation has been hypothesized to counteract hallucinogenic activity (Halberstadt and Geyer, 2011; Nichols, 2004), and lower 5-HT 1A receptor stimulation for the NBOMe drugs may further enhance their hallucinogenic drug properties. N-2-methoxybenzyl substitution increased 5-HT 2B activation, but this is likely not relevant for the psychotropic properties of the NBOMe drugs (Blaazer et al., 2008). However, 5-HT 2B receptors have been implicated in substance-induced heart valve fibrosis (Bhattacharyya et al., 2009; Setola et al., 2003), and the 2C and NBOMe drugs may therefore have cardiac toxicity if used chronically. "
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    ABSTRACT: Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB, and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine (DA), and serotonin (5-HT) uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, DA, and 5-HT from monoamine-preloaded cells, monoamine receptor binding affinity, and 5-HT2A and 5-HT2B receptor activation. All of the benzofurans inhibited NA and 5-HT uptake more than DA uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated receptor 1 (TAAR1 ), similar to classic amphetamines. Most benzofurans were partial 5-HT2A agonists similar to MDMA, but also 5-HT2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 receptors and also bound to TAAR1 . Despite very similar structures, differences were found in the pharmacological profiles of the different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with serotonergic receptors. This pharmacological profile likely results in MDMA-like entactogenic psychoactive properties. However, benzofurans produce 5-HT2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 03/2015; 172(13). DOI:10.1111/bph.13128 · 4.84 Impact Factor
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    • "Several of these compounds displayed affinities and potencies in the picomolar range with varying levels of selectivity for the 5-HT 2A R, with the m o s t s e l e c t i v e c o m p o u n d , 2 -( [ 2 -( 4 -c y a n o -2 , 5 dimethoxyphenyl )ethylamino]methyl)phenol (25CN-NBOH, Fig. 1), exhibiting a 100-fold greater binding affinity for 5- HT 2A R over 5-HT 2C R (Hansen et al. 2014), and a 46-fold selectivity for 5-HT 2A R over 5-HT 2B R (Hansen 2011). The structure of 25CN-NBOH is similar to that of other N-benzyl substituted phenethylamines currently emerging as drugs of abuse, including 25B-NBOMe, 25C-NBOMe, and 25I- NBOMe (Lawn et al. 2014), all of which are potent hallucinogens in man, consistent with the finding that N-benzyl substitutions dramatically increase affinity for 5-HT 2A R in vitro and in vivo (Blaazer et al. 2008; Nichols et al. 2008; Advisory Council on the Misuse of Drugs ACMD 2013; Halberstadt and Geyer 2014). "
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    ABSTRACT: Rationale 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]-methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT 2A receptors in vitro, but has not been behaviorally characterized. Objective 25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination. Methods Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT 2A antagonist M100907 or 3.0 mg/kg 5-HT 2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization. Results 25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55 %) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals. Conclusions 25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT 2A receptor is an important site of agonist action for this compound in vivo.
    Psychopharmacology 09/2014; 232(6). DOI:10.1007/s00213-014-3739-3 · 3.88 Impact Factor
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    • "NBOMe substances were first synthesized in 2003 by Ralph Heim at the Free University of Berlin and then they were further studied by David Nichols in 2008 (Heim, 2003; Nichols et al., 2008). These substances are highly potent hallucinogens even in doses of micrograms, as the N-benzyl substitution of phenethylamines dramatically increases their affinity with the serotonin 2A (5-HT 2A ) receptors (Braden et al., 2006; Blaazer et al., 2008; Ettrup et al., 2011; Halberstadt & Geyer, 2014; Nichols et al., 2008). As NBOMe substances act via 5-HT 2A receptors, they present a significant abuse potential and have been regarded as alternatives to LSD (ACMD, 2013; Halberstadt & Geyer, 2014). "
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    ABSTRACT: Abstract Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply until these compounds become classified as scheduled. 2C-I-NBOMe or 25I-NBOMe is the N-benzyl-derivative of the iodo-substituted dimethoxy-phenethylamine (2C-I) that appeared recently in the drug market under the street name "N-Bomb". Due to its high potency, intoxications and fatal cases related to 2C-I-NBOMe use are increased worldwide. The use and trafficking of this substituted phenethylamine is banned only in some countries. A comprehensive review was performed using PubMed and Medline databases, together with additional non-peer reviewed information sources, including books and publications of state authorities in different countries, regarding chemistry, availability, pharmacology, and toxicology of 2C-I-NBOMe. Intoxications or lethal cases, published or reported, as well as the current legislation on this newly introduced drug are also reviewed.
    Drug and Chemical Toxicology 05/2014; 38(1). DOI:10.3109/01480545.2014.911882 · 1.23 Impact Factor
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