Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT₂A receptors, in mice

Abstract

Rationale: 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally characterized.

Objective: 25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination.

Methods: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT2A antagonist M100907 or 3.0 mg/kg 5-HT2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization.

Results: 25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55 %) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals.

Conclusions: 25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT2A receptor is an important site of agonist action for this compound in vivo.

Figure 1

Structures of 25CN-NBOH (left) and R(−)-DOI (right).

Figure 2

Biphasic dose-dependent effects of R(−)-DOI (black circles) and 25CN-NBOH (grey triangles) on head twitch behavior in NIH Swiss mice. Black diamonds represent 25CN-NBOH-elicited head twitch behavior after pretreatment with 0.01 mg/kg M100907, while the white inverted triangle represents 25CN-NBOH-elicited head twitch behavior following pretreatment with 3.0 mg/kg RS102221. Asterisks indicate significant differences from saline, hash marks indicate significant differences from the same dose of DOI, and bullseyes indicate differences from the same dose of 25CN-NBOH (without antagonist pretreatment). Abscissa: Dose of DOI or 25CN-NBOH, expressed as mg/kg on a log scale. Ordinate: Mean head twitches recorded over a 10 minute observation period.

Figure 3

Head twitch behavior elicited by 1.0 mg/kg R(−)-DOI following pretreatment with saline (white circle) or various doses of 25CN-NBOH (black circles.) Asterisks indicate significant differences from saline pretreatment, while hash marks indicate significant differences from lower pretreatment doses of 25CN-NBOH. Abscissa: Dose of 25CN-NBOH, expressed as mg/kg on a log scale, and administered as a pretreatment 15 min prior to R(−)-DOI injection. Ordinate: as described in Figure 2.

Figure 4

Left panel - Discriminative stimulus effects of R(−)-DOI (black circles), 25CN-NBOH (grey triangles), and 25CN-NBOH following pretreatment with M100907 (white triangles) in mice trained to discriminate 0.3 mg/kg R(−)-DOI from saline. Asterisks indicate significant differences from saline, while hash marks indicate significant differences from the DOI training dose. Abscissa: Cumulative dose of DOI or 25CN-NBOH expressed as mg/kg on a log scale. Ordinate: percent of total responses emitted on the R(−)-DOI-appropriate lever. Right panel – Response rates (per second) obtained during substitution testing with cumulative doses of R(−)-DOI and 25CN-NBOH. Fractions represent number of animals completing the response requirement at a given dose, if less than 6. Abscissa: ‘S1–S4' represents four discrete saline injections administered across four components of a substitution session. Numbers refer to cumulative doses of drugs during substitution sessions, expressed as mg/kg on a log scale. Ordinate: response rates, expressed as lever presses per second.

Figure 5

Left panel - Discriminative stimulus effects of M100907 (black circles), ketanserin (white circles) and 25CN-NBOH (grey triangles) in mice trained to discriminate 0.1 mg/kg M100907 from saline. Asterisks indicate significant differences from saline, while hash marks indicate significant differences from the M100907 training dose. Abscissa and ordinate as described in Figure 4. Right panel – Response rates (per second) obtained during substitution testing with cumulative doses of M100907, ketanserin and 25CN-NBOH. Abscissa and ordinate as described in Figure 4.