Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups

Abstract

Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoal kanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]-8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, 1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-am inopropane (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [125I]DOI and [3H]ketanserin binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED50 of 61 nmol/kg and had Kj values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these new analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT2 receptors.

Structure–activity relationships of serotonin 5‐HT2A agonists

“…A similar approach to tethering of the 2-methoxy into a dihydrofuran also led to a very potent compound (49), 83 but when both the 2-and 5-methoxy functions were incorporated into dihydrofuran rings, the result was a series of exceptionally potent 5-HT 2A/2C agonists exemplified by 50, 83,84 which had an affinity of 0.48 nM for the cloned human 5-HT 2A receptor. Aromatization of the dihydrofuran rings to afford 51 led to even further enhancement of affinity and potency ( Figure 21).…”

Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of 3,4-(Methylenedioxy)amphetamine (MDA)

“…16,17 For those compounds that completely substituted for a training drug, potencies were calculated as ED 50 values with 95% confidence intervals.…”

“…The procedures for the drug discrimination assays were exactly as described previously. 16,17 Training drugs were (+)-amphetamine sulfate (1.0 mg/kg), (+) -N-methyl-1-(1,3-benzodioxol …”

2C or Not 2C: Phenethylamine Designer Drug Review

“…The structure of 2Cs responsible for the hallucinogenic effects consists of a primary amine separated by two carbon atoms from the phenyl ring, methoxy groups at positions 2 and 5 on the phenyl ring, and a hydrophobic substituent at position 4 on the phenyl ring ( Fig. 1) [3,15,16]. It is possible to create new hallucinogenic 2Cs by placing different substituents on the aromatic ring at positions 2, 4, or 5 [5,16].…”

“…1) [3,15,16]. It is possible to create new hallucinogenic 2Cs by placing different substituents on the aromatic ring at positions 2, 4, or 5 [5,16].…”