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
January 26, 2001
James J. Chambers, Deborah Kurrasch‐orbaugh, Matthew Parker et al.
98 citations
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.
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
February 24, 1998
Matthew Parker, Danuta Marona‐lewicka, Deborah M. Kurrasch et al.
25 citations
Adding a methyl group to the 2 or 5 position of the ring of MDA produces compounds that are more potent and more selective than MDA itself at releasing serotonin in rat brain tissue. The 2-methyl and 5-methyl derivatives were tested in rats trained to distinguish serotonin-releasing drugs from saline, confirming their activity in living animals. These compounds are among the most potent serotonin-releasing agents known and may serve as leads for developing antidepressants that work by releasing serotonin rather than blocking its reuptake.