Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity
Journal of Medicinal Chemistry May 1, 1998 Aaron Monte, Danuta Marona‐lewicka, Mechelle M. Lewis et al. 20 citations
A series of racemic naphthofurans were synthesized as hybrid molecules of phenethylamine and tryptamine/ergoline hallucinogens. Although the compounds were expected to have high affinity for serotonin 5-HT2A/2C receptors, they instead showed low affinity for those receptors and unexpected affinity for muscarinic receptors. One compound, 4d, had affinities of 12-33 nM at all muscarinic M1-M5 sites and fully antagonized carbachol at M1 and M2 receptors. The naphthofurans lacked LSD-like activity in a drug discrimination paradigm in rats, indicating that the tricyclic naphthofuran nucleus is not bioisosteric with LSD and that hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation, contrary to previous hypotheses.