Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

Abstract

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.

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

“…Within the 2C or NBOMe drug series, para-phenyl substitutions compared with 2C-H or 25H-NBOMe, respectively, enhanced 5-HT 2 receptor binding and activation potency, which was expected based on previous studies (Blaazer et al, 2008;Eshleman et al, 2014;Hansen et al, 2014;Shulgin and Shulgin, 1991). Interestingly, 5-HT 2A receptor activation potency increased with the size of the 4-substituent (2C-D < 2C-E < 2C-P) within the 2C series (Blaazer et al, 2008;Eshleman et al, 2014), Thus, NBOMe drugs are unlike LSD, which is a potent 5-HT 1A receptor ligand and full agonist at 5-HT 1A receptors (Nichols, 2004).…”

“…Interestingly, 5-HT 2A receptor activation potency increased with the size of the 4-substituent (2C-D < 2C-E < 2C-P) within the 2C series (Blaazer et al, 2008;Eshleman et al, 2014), Thus, NBOMe drugs are unlike LSD, which is a potent 5-HT 1A receptor ligand and full agonist at 5-HT 1A receptors (Nichols, 2004). Importantly, 5-HT 1A receptors have been shown to contribute to the discriminative stimulus effects of some hallucinogens (Halberstadt, 2015;Nichols, 2004).…”

“…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.…”

“…Pharmacological interactions between NBOMe drugs and 5-HT 2 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.…”

Structure–activity relationships of serotonin 5‐HT2A agonists

“…To complement the discussion here the reader is encouraged to read an earlier review on this topic, 43 as well as a more recent extensive review on phenethylamine 5-HT 2A agonists. 44 The prototype for this class is mescaline 32, a simple trimethoxy phenethylamine that was first isolated from the peyote cactus, Lophophora williamsii. Like all known 5-HT 2A agonists it is hallucinogenic in man, but has very low potency, a typical oral dose of the sulfate being in the range 250-400 mg.…”