Binding of phenylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity

Abstract

Certain phenylalkylamine derivatives have been considered to bind selectively at 5-HT2 serotonin receptors. It is now recognized that the most widely used derivatives, i.e., 1-(2,5-dimethoxy-4-X-phenyl)-2-aminopropanes where X = Me (DOM), Br (DOB), and I (DOI) (1-3, respectively) also bind at the more recently identified population of serotonin 5-HT1C receptors. The purpose of the present investigation was to determine whether simple phenylalkylamines bind selectively at one population of receptors over the other. An examination of 34 derivatives reveals (i) similar structure-affinity relationships and (ii) a significant correlation (r = greater than 0.9, n = 25) between 5-HT1C and 5-HT2 affinity. None of the compounds included in the present study displayed more than a 10-fold selectivity for one population of these receptors over the other; the results suggest that these compounds (including the widely used 5-HT2 agonists DOB and DOI) are 5-HT1C/5-HT2 agents.

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors

“…Among the best known are 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-methylphenethylamine (2C-D), the ␣-demethylated analogs of DOI, DOB, and DOM, respectively. The data available for these phenethylamines show that their affinities for 5-HT 2A receptors are similar to those of their phenylisopropylamine counterparts, whereas different functional models have shown that their efficacies are lower than those of their ␣-methylated analogs (Glennon et al, 1992;Nichols et al, 1994;Acuñ a-Castillo et al, 2002;Parrish et al, 2005). Again, with few exceptions, most in vitro studies on these compounds examined only PLC-mediated responses.…”

Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats

“…This compound is equipotent as a releaser of dopamine, norepinephrine and 5-HT [4], It also shows low affinity for 5-HT 2 receptors [15]. However, with respect to 5-HT release, 4-MA was significantly more potent compared to amphetamine [4].…”

“…In present experiments, when animals were pre-treated with ketanserin or haloperidol (at doses that did not affect basal locomotor activity), the hyperlocomotion of 4-MA was partially inhibited, suggesting both 5-HT and dopamine take part in this effect. According to previously published studies [15] The main problem associated to 4-MA exposure is the acute toxicity of this drug, which seems to be linked to hyperthermia. For this reason, we focused our attention on the effects of 4-MA on body temperature.…”

Antagonism of a PCP Drug Discrimination by Hallucinogens and Related Drugs

“…Many drugs with agonist properties at 5-HT2A receptors also have agonist properties at 5-HT2C and other receptor subtypes; this is clearly the case with LSD (Marek and Aghajanian 1996), DOM (Glennon et al 1992), and DMT (Smith et al 1998). Therefore, it is difficult to attribute the behavioral or neurotoxic effects of these compounds exclusively to their actions at the 5-HT2A receptor.…”