N-Methyl derivatives of the 5-HT2 agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane

Abstract

1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) is a serotonin (5-HT) agonist that displays a high affinity and selectivity for a certain population of central 5-HT binding sites (i.e., 5-HT2 sites). In the present study, (a) an enantiomeric potency comparison was made for the optical isomers of DOB and (b) the activity of N-monomethyl-,N,N-dimethyl-, and N,N,N-trimethyl-DOB was examined. (R)-(-)-DOB (Ki = 0.39 nM) was found to have 6 times greater affinity than its S-(+) enantiomer at [3H]DOB-labeled (rat cortical homogenates) 5-HT2 sites; N-methylation of racemic DOB resulted in a decrease in affinity that was at least 1 order of magnitude per methyl group. Similar results were obtained in an in vivo drug discrimination paradigm with rats as subjects and (R)-(-)-DOB (0.2 mg/kg) as the training drug. Thus, the R-(-) isomer of DOB is more active than its S-(+) enantiomer and than any of the possible N-methyl derivatives of DOB, both with respect to affinity at central 5-HT2 binding sites and with respect to potency in the behavioral (i.e., stimulus generalization) studies.

Radiosynthesis and in vitro evaluation of the 5HT2 receptor ligand [N-11C-methyl]-1-[2,5-dimethoxy-4-iodophenyl]-2-methylaminopropane for PET

“…This observation is in agreement with other hallucinogenic phenylalkylamines where a primary amine exhibited higher hallucinogenic potency which correlates with higher affinity to 5-HT 2 receptors [19]. It has been reported that the N,N-dimethyl and N-monopropyl analogs of DOB (1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane), the brominated counterpart of DOI, showed significant decrease in 5-HT 2A receptor affinity [20,21]. Glennon et al [19] compared affinities of DOB, the N-monomethyl analog and the N-benzyl derivative for 5-HT 2A and 5-HT 2C .…”

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

“…[171] Binding studies using [ 3 H]DOB (16) as a radioligand indicated R-(À)-16 (K i = 0.39 nm) as the highest affinity enantiomer, followed by (AE )-16 (K i = 0.79 nm), and S-(+)-16 (K i = 2.3 nm). [172] Similarly, a DD assay in the same study found R-(À)-16 to be~10 times more potent than S-(+)-16. The same pattern was seen for compound 17, where the R-(À) isomer is 2-3 times as potent as the S-(+) enantiomer.…”

“…N-alkylation or N,N-dialkylation proved detrimental to the potency of most phenylalkylamines. [172,174,175] An exception was found in a series of N-benzyl substituted phenylalkylamines; [176] affinity studies comparing 2C-B (11) with its N-benzylated analogues (29-31) revealed an approximate twofold increase in binding affinity for [ 125 I]DOI labeled 5-HT 2A receptors. Moreover compounds 29-31 showed increased subtype selectivity (> 100 fold) for 5-HT 2A over 5-HT 2C receptors, however the question whether 29-31 act as agonists or antagonists has not been addressed.…”

Attenuation of nicotine?s discriminative stimulus effects in rats and its locomotor activity effects in mice by serotonergic 5-HT2A/2C receptor agonists

“…DOB was administered i.p. 15 min prior to the test session (Glennon et al 1987) and 8-OH-DPAT was administered s.c. 15 min prior to the test session with the 0.3-mg/kg training dose of nicotine.…”