Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists
James J. Chambers, Deborah Kurrasch‐orbaugh, Matthew Parker, David E. Nichols
Journal of Medicinal Chemistry January 26, 2001 DOI: 10.1021/jm000491y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Enantiomer Stereochemistry Potency Stereoselectivity Acylation Ketone Receptor Partial agonist Intrinsic activity In vitro Biochemistry Organic chemistry |
| Citations | 98 |
| Key points | Compounds with a fully aromatic linear tricyclic nucleus are among the highest-affinity ligands for the 5-HT(2A) receptor reported to date. |
Abstract
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.
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| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 27
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- Pharmacological profile of novel psychoactive benzofurans British Journal of Pharmacology March 13, 2015
- 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry September 21, 2006
- Metabolism of designer drugs of abuse: an updated review. Current Drug Metabolism June 1, 2010
- Designer Drugs on the Internet: A Phenomenon Out-of-Control? The Emergence of Hallucinogenic Drug Bromo-Dragonfly Current reviews in clinical and experimental pharmacology May 1, 2011
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Cites 7
- Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Journal of Medicinal Chemistry 1996
- Dihydrobenzofuran Analogues of Hallucinogens. 4. Mescaline Derivatives Journal of Medicinal Chemistry September 1, 1997
- A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor Journal of Medicinal Chemistry December 1, 1998
- Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes Journal of Medicinal Chemistry March 1, 1995
- Effect of a Chiral 4-Alkyl Substituent in Hallucinogenic Amphetamines Journal of Medicinal Chemistry September 1, 1995
and 2 more in the library