Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity
Aaron Monte, Danuta Marona‐lewicka, Mechelle M. Lewis, Richard B. Mailman, David B. Wainscott, David L. Nelson, David E. Nichols
Journal of Medicinal Chemistry May 1, 1998 DOI: 10.1021/jm980076u (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Phenethylamines Muscarinic acetylcholine receptor Stereochemistry Ketanserin Hallucinogen Partial agonist 5-ht2 receptor 5-HT Receptor Pharmacology Biochemistry |
| Citations | 20 |
| Key findings | The naphthofurans lack LSD-like activity, suggesting that hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation. |
Abstract
A series of substituted racemic naphthofurans were synthesized as "hybrid" molecules of the two major prototypical hallucinogenic drug classes, the phenethylamines and the tryptamines/ergolines. Although it was hypothesized that these new agents might possess high affinity for the serotonin 5-HT2A/2C receptor subtypes, unexpected affinity for muscarinic receptors was observed. The compounds initially synthesized for this study were (+/-)-anti- and syn-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan (4a,b), respectively, and their 8-bromo derivatives 4c,d, respectively. The brominated primary amines 4c,d were assayed initially for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0. 08 mg/kg). Also, 4c,d were evaluated for their ability to compete against agonist and antagonist radioligands at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. After the syn diastereomers were found to have the highest activity in these preliminary assays, the N-alkylated analogues syn-N,N-dimethyl-4-amino-6-methoxy-2a,3,4, 5-tetrahydro-2H-naphtho[1,8-bc]furan (4e) and syn-N, N-dipropyl-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1, 8-bc]furan (4f) were prepared and assayed for their affinities at [3H]ketanserin-labeled 5-HT2A and [3H]-8-OH-DPAT-labeled 5-HT1A sites. All of the molecules tested had relatively low affinity for serotonin receptors, yet a preliminary screen indicated that compound 4d had affinity for muscarinic receptors. Thus, 4b,d,e were evaluated for their affinity at muscarinic M1-M5 receptors and also assessed for their functional characteristics at the M1 and M2 isoforms. Compound 4d had affinities of 12-33 nM at all of the muscarinic sites, with 4b,e having much lower affinity. All three compounds fully antagonized the effects of carbachol at the M1 receptor, while only 4d completely antagonized carbachol at the M2 receptor. The fact that the naphthofurans lack LSD-like activity suggests that they do not bind to the serotonin receptor in a way such that the tricyclic naphthofuran nucleus is bioisosteric with, and directly superimposable upon, the A, B, and C rings of LSD. This also implies, therefore, that the hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation for these two chemical classes, contrary to previous hypotheses.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 6
- 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry September 21, 2006
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
- Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands Journal of Medicinal Chemistry July 1, 2003
- C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor Journal of Medicinal Chemistry June 21, 2006
- Behavioral profiles in rats distinguish among "ecstasy," methamphetamine and 2,5-dimethoxy-4-iodoamphetamine: Mixed effects for "ecstasy" analogues. Behavioral Neuroscience October 1, 2010
and 1 more in the library
Cites 9
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- [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for the 5-HT2 receptor in rat frontal cortex. Pharmacology, Biochemistry, and Behavior 1990
- 2,3-Dihydrobenzofuran analogs of hallucinogenic phenethylamines Journal of Medicinal Chemistry 1991
- Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines Journal of Medicinal Chemistry December 1, 1975
- Benzofuran bioisosteres of hallucinogenic tryptamines. Journal of Medicinal Chemistry May 1, 1992
and 4 more in the library