Journal of Medicinal Chemistry
January 1, 1996
Aaron Monte, Danuta Marona‐lewicka, Matthew Parker et al.
106 citations
A series of eight new phenylalkylamine derivatives with conformationally restricted dihydrofuran rings were synthesized and tested in rats. One compound, 7b, substituted for LSD in a drug discrimination assay with an ED50 of 61 nmol/kg and bound to 5-HT2 receptors with nanomolar to subnanomolar affinity, making it among the most potent hallucinogen-like phenylalkylamines reported. All compounds with a hydrophobic substituent para to the alkylamine side chain matched or exceeded the activity of flexible parent compounds. The results suggest the dihydrofuran rings model the active binding conformations of methoxy groups and provide information about agonist binding topography in serotonin 5-HT2 receptors.
Journal of Medicinal Chemistry
September 1, 1997
Aaron Monte, Steve R. Waldman, Danuta Marona‐lewicka et al.
89 citations
Conformationally restricted bioisosteres of mescaline's methoxy groups—dihydrobenzofuran (8) and tetrahydrobenzodifuran (9)—were synthesized and tested against mescaline (1) in drug discrimination assays in rats trained to discriminate LSD from saline. Neither 8 nor 9 substituted for LSD: only 50% of rats given 8 and 29% given 9 selected the drug lever, whereas mescaline fully substituted (ED50 = 33.5 mumol/kg). All compounds showed micromolar affinity for 5-HT1A and 5-HT2A receptors in rat brain homogenate, but rank order of affinities at 5-HT2A sites reversed their behavioral potency. At 5-HT2A receptors, 8 and 9 were less efficacious (61% and 45% of maximal response), while all compounds matched serotonin's efficacy at 5-HT2C receptors.
Journal of Medicinal Chemistry
December 1, 1998
Matthew Parker, Danuta Marona‐lewicka, Virginia L. Lucaites et al.
69 citations
A novel (benzodifuranyl)aminoalkane compound was synthesized and evaluated for activity at the 5-HT2A receptor. The compound exhibited extremely potent activity, with a Ki value of 0.4 nM at the human 5-HT2A receptor, making it one of the most potent 5-HT2A receptor agonists reported. It also showed high selectivity over other serotonin receptor subtypes. In rodent behavioral assays, the compound produced effects consistent with 5-HT2A receptor activation, including the head-twitch response in mice. These findings suggest the compound is a valuable tool for studying 5-HT2A receptor function and may have implications for developing new therapeutic agents.
Journal of Medicinal Chemistry
March 1, 1999
Joseph B. Blair, Danuta Marona‐lewicka, Arthi Kanthasamy et al.
63 citations
Two thienopyrrole compounds, designed as structural replacements for the indole ring in N,N-dimethyltryptamine (DMT), were synthesized and tested. Neither compound produced LSD-like effects in rats trained to discriminate LSD or DOI, even at high doses. However, both fully substituted for a 5-HT1A receptor agonist and caused behaviors consistent with 5-HT1A activation, such as serotonin syndrome and salivation. At the 5-HT2A receptor, one compound had twice the affinity of the other, while at 5-HT2B and 5-HT2C receptors the pattern reversed. The thienopyrrole replacement thus failed to mimic DMT's activity at 5-HT2 receptors but enhanced activity at the 5-HT1A receptor, indicating that serotonin receptor subtypes respond differently to subtle electronic changes in the aromatic ring system.
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.