Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists.
The affinity of ligands for either the 5-HT(2A) or 5-HT(2C) agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy compounds. The pure enantiomers of these arylalkylamines were obtained by enantiospecific synthesis that involved acylation of the heterocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstrated modest stereoselectivity at the two receptors. Several general trends within these classes of new compounds were observed during their pharmacological investigation. For most pairs of optical isomers tested, the R-enantiomers of the compounds containing heterocycle 7 bound with only slightly higher affinity than their S-antipodes at the 5-HT(2A) and 5-HT(2C) receptors. Likewise, functional studies indicated that the R-enantiomers generally displayed increased potency compared to the S-enantiomers. Aromatization of the dihydrofuran rings of these arylalkylamines further increased affinity and potency. Only a few compounds were full agonists with most of them possessing intrinsic activities in the range of 60-80%. These compounds with a fully aromatic linear tricyclic nucleus are some of the highest-affinity ligands for the 5-HT(2A) receptor reported to date.
Chambers
J J
JJ
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Kurrasch-Orbaugh
D M
DM
Parker
M A
MA
Nichols
D E
DE
D016475:3T3 Cells; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000662:Amphetamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000662:Amphetamines; D005663:Furans; D007295:Inositol Phosphates; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000409:Alanine