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
March 1, 1995
Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al.
25 citations
Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.
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.