Behavioral and serotonin receptor properties of 4-substituted derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane

Abstract

The serotonin (5-HT) receptor affinities and behavioral (discriminative stimulus) properties of a series of 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropanes (2,5-DMA) were investigated. The substituents at the 4-position included H, OMe, OEt, Me, Et, F, Br, I, and NO2. Substituent lipophilicities (pi values) of these functionalities appear to have a minimal effect on either 5-HT receptor affinity or behavioral activity. Those derivatives previously found to be most potent in human studies possess significant affinity for 5-HT receptors. Furthermore, when rats trained to discriminate (+/-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline were used, generalization was found to occur upon administration of the 4-substituted 2,5-DMA derivatives. Because a direct relationship exists between the ED50 values obtained from these discrimination studies and human hallucinogenic potencies, the discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

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

“…[145] a-Methylation of the phenethylamines to their corresponding phenylisopropylamines leads to the most potent compounds, such as DOM (15), DOB (16), and DOI (17). [146][147][148] A significant increase in potency was observed from compound 10 (ED 50 = 5.6 mmol kg À1 ) to (AE )-15 (ED 50 = 1.8 mmol kg À1 ) in DD studies, [149] and in human clinical studies. [117,144] However, an affinity study using rat brain […”

Drug‐induced discrimination: A description of the paradigm and a review of its specific application to the study of hallucinogenic agents

“…There- fore, an investigation was undertaken in order to determine which of a series of phenalkylamines was capable of producing effects similar to those of 5-)Me DMT. The training dose employed for 5-OMe DMT was 3.0 mg/kg; the phenalkylamines included 36 phenylisopropylamines and/or isomers. 71 The results of this study allowed the differentiation of phenalkylamine derivatives on the basis of their stimulus properties.…”

“…However, there is a significant ( r = 0.964) correlation between the ED,,values of 1 4 phenylisopropylamines and their total human hallucinogenic dose. 36 Although it is not being suggested that the use of the discriminative stimulus paradigm, with DOM (1.0 mglkg) as the training drug, serves as a model or predictor of human hallucinogenic potency, there certainly exists a relationship between human hallucinogenic potency and discrimination-derived data. To further challenge this relationship, ED,, values were determined for several additional agents and Figure 7 shows a plot of log Iltotal human hallucinogenic dose (pmoles) vs log I/ED,, (pmbleslkg) for the extended series of compounds.…”

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

“…Therefore, it appears that inhibition of MAO is not involved in the ocular hypotensive response observed for 5-HOAMT, 5-MeOAMT, and R-DOI. 5-MeODMT (Weil and Davis, 1994), 5-MeOAMT (Kantor et al, 1980), and R-DOI (Glennon et al, 1982) have been shown to enter the central nervous system following systemic dosing, suggesting that a centrally mediated mechanism may be responsible for the reduction in IOP observed with 5-HT 2 agonists. However, the nonselective peripheral 5-HT 2 agonists 5-HOAMT (Baudrie and Chaouloff, 1992;Okada et al, 1995) and 5-HODMT (McBride, 2000) also decreased IOP in the monkey following topical administration.…”