Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines

Abstract

A homologous series of 4-alkyl-2,5-dimethoxyphenylisopropylamines (alkyl = H through n-C5H11 and t-C4H9) was synthesized and compared with mescaline as serotonin agonists in a sheep umbilical preparation. The three-carbon homolog 6d was found to be the most potent of the straight-chain series in accordance with its observed psychotomimetic effectiveness in man.

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

“…In rats and humans, DOET and DOI are ~10-fold more potent than TMA-2 and ~50-fold more potent than mescaline (see Table 4), which parallel our findings in mice. The fact that DOTB did not alter exploratory or investigatory behavior in mice is consistent with evidence that DOTB is not hallucinogenic (Shulgin and Dyer, 1975), and does not induce hallucinogen-like behavioral effects in rodents (Kulkarni, 1973; Morin et al, 1975; Glennon et al, 1982). DOTB has high affinity for the 5-HT 2A receptor (Table 4), but exhibits weak efficacy, inducing phosphoinositide hydrolysis with ~50% of the intrinsic efficacy of R -(-)-DOB (Glennon et al, 1992).…”

“…The relative potencies of the phenylalkylamines in the BPM (DOPR ≈ DOI ≈ DOET > TMA-2 > mescaline) are consistent with their potencies for eliciting DOM-like discriminative stimulus effects in rats (Glennon et al, 1983) and hallucinogenic effects in humans (Shulgin and Dyer, 1975; Shulgin and Shulgin, 1991). In rats and humans, DOET and DOI are ~10-fold more potent than TMA-2 and ~50-fold more potent than mescaline (see Table 4), which parallel our findings in mice.…”

“…Likewise, administration of the conformationally restricted benzocyclobutene derivative TCB-2, previously shown to be a potent 5-HT 2A agonist (McLean et al, 2006b), also provoked hyperactivity. By contrast, DOTB, a homologue of DOET and DOPR that exhibits very low efficacy at the 5-HT 2A receptor (Glennon et al, 1992) and is inactive as a hallucinogen (Shulgin and Dyer, 1975), failed to alter any of the behavioral measures tested. To test for involvement of the 5-HT 2A receptor in the behavioral response to mescaline and TCB-2, we compared the effects of these substances in WT and 5-HT 2A receptor KO mice on a C57 background.…”

“…Given these discrepant findings, we tested a larger series of phenylalkylamine hallucinogens and related substances (Figure 1) in the BPM to determine whether those compounds increase locomotor activity by activating the 5-HT 2A receptor. In addition, to determine whether the 5-HT 2A -mediated increase in locomotor activity is specific to phenylalkylamines with hallucinogenic activity, we tested the nonhallucinogenic DOM homologue 2,5-dimethoxy-4- tert -butylamphetamine (DOTB; Shulgin and Dyer, 1975), which acts as a partial agonist at the 5-HT 2A receptor (Glennon et al, 1992). …”

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

“…[163] Yet later work using [ 3 H]ketanserin as a radioligand for 5-HT 2 receptors in rat brain homogenate revealed significantly increased binding affinities with the more lipophilic derivatives; n-hexyl and n-octyl derivatives showed the highest binding affinity. After in vitro testing, these derivatives were found to act as 5-HT 2 receptor antagonists.…”