Modifying the 2,5-oxygen substituents typical of hallucinogenic amphetamines such as DOB enhanced ligand affinity for 5-HT(2A) and 5-HT(2C) agonist binding sites. Restricting flexible 2,5-dimethoxy groups into fused dihydrofuran rings generally increased potency. Pure enantiomers were synthesized via enantiospecific acylation, ketone reduction, and N-deprotection. R-enantiomers bound with slightly higher affinity than S-enantiomers at both receptors and generally showed greater potency in functional studies. Aromatization of dihydrofuran rings further increased affinity and potency. Most compounds were partial agonists with intrinsic activities of 60-80%. Compounds with a fully aromatic linear tricyclic nucleus are among the highest-affinity 5-HT(2A) receptor ligands reported.
Conformationally constrained tetrahydronaphthofurans were designed to study the optimal shape of the 2-aminoethyl moiety in phenethylamine-type serotonin 5-HT(2A) receptor agonists. In vitro assays showed that benzofuran-containing analogues (6a and 6b) had significantly higher affinity for 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors than benzodihydrofuran-containing compounds. The most potent compound, 6b, had K(i) values of 2.6 nM at 5-HT(2A) and 1.1 nM at 5-HT(2C) cloned rat receptors. Despite high affinity, these naphthofuran compounds lacked high intrinsic activity at the 5-HT(2A) receptor in the phosphoinositide hydrolysis assay. Compound 6b failed to substitute for LSD in a rat drug discrimination assay, typical for low intrinsic activity compounds. Conformational constraint produced high-affinity partial agonists, but full receptor activation requirements remain unidentified.
A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.