Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2C Receptors

Abstract

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT) 2A/2C agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A 2 (PLA 2 )] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA 2 and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT 2A or 5-HT 2C receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT 2C receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT 2A receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT 2C receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT 2C receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA 2 -specific at the 5-HT 2A receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT 2A receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

Psychedelics

“…Some of these differences are noteworthy; for example, in psilocin, the potency for activating AA release was nearly 30-fold greater than for stimulating PI turnover. Moya et al (2007) compared two homologous series of substituted psychedelic phenethylamines and phenylisopropylamines for signaling at the 5-HT 2A receptor through PLC and PLA 2 responses. They employed Chinese hamster ovary (CHO)-FA4 cells stably expressing the human 5-HT 2A receptor that had similar maximal responses for inositol phosphate (IP) accumulation and AA release in response to serotonin.…”

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…Consistent within other hallucinogens, no clear correlation was found between binding affinity to the 5-HT 2A receptor and its functional activation potency (Nichols et al, 2015). Importantly, 5-HT 2A receptor activation is measured using various in vitro assays that reflect the activation of 17 different second messenger systems (Moya et al, 2007;Nichols, 2004), and these measures may apparently not reflect the mechanisms that mediate the subjective effects of these hallucinogens.…”

“…-Methyl-5-HT and fluoro-α-methyltryptamines were shown to be more potent than their non--methylated analogs in inducing hallucinogen-typical head-twitch responses in mice (Nakagawasai et al, 2004;Tadano et al, 1995). Similarly, the α-methylation of phenethylamines increased 5-HT 2A receptor stimulation efficacy and head-twitch responses (Moya et al, 2007).…”

Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

“…The increase of monoamine contents in brain, especially 5-HT, is known to cause several abnormal behaviors in animals, such as HTR and head-weaving (Kim et al, 1998). It is also reported that HTR is induced by 5-HT 2A receptor stimulation in the prefrontal cortex (Willins and Meltzer, 1997;González-Maeso et al, 2003;Nakagawasai et al, 2004;Moya et al, 2007). It was documented for the first time that 5-HT 7 receptor stimulation is also able to produce HTR (Figure 2).…”