Substituted naphthofurans as hallucinogenic phenethylamine -Ergoline hybrid molecules with unexpected muscarinic antagonist activity

Aaron P. Monte, Danuta Marona-Lewicka, Mechelle Lewis, Richard Mailman, David B. Wainscott, David L. Nelson, David E. Nichols

Research output: Contribution to journalArticle

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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-HT(2A)/(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 mines 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-HT(2A), 5-HT(2B), and 5-HT(2C) 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- HT(2A) and [3H]-8-OH-DPAT-labeled 5-HT(1A) 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.

Original languageEnglish (US)
Pages (from-to)2134-2145
Number of pages12
JournalJournal of Medicinal Chemistry
Volume41
Issue number12
DOIs
StatePublished - Jun 4 1998

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Ergolines
Muscarinic Antagonists
Lysergic Acid Diethylamide
Serotonin
Receptor, Serotonin, 5-HT2C
Phenethylamines
Serotonin Receptors
Carbachol
Muscarinic Receptors
Muscarinic M5 Receptors
Muscarinic M1 Receptors
Tryptamines
Hallucinogens
Receptor, Serotonin, 5-HT2A
8-Hydroxy-2-(di-n-propylamino)tetralin
Ketanserin
Cholinergic Agents
Protein Isoforms
phenethylamine
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Monte, Aaron P. ; Marona-Lewicka, Danuta ; Lewis, Mechelle ; Mailman, Richard ; Wainscott, David B. ; Nelson, David L. ; Nichols, David E. / Substituted naphthofurans as hallucinogenic phenethylamine -Ergoline hybrid molecules with unexpected muscarinic antagonist activity. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 12. pp. 2134-2145.
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Substituted naphthofurans as hallucinogenic phenethylamine -Ergoline hybrid molecules with unexpected muscarinic antagonist activity. / Monte, Aaron P.; Marona-Lewicka, Danuta; Lewis, Mechelle; Mailman, Richard; Wainscott, David B.; Nelson, David L.; Nichols, David E.

In: Journal of Medicinal Chemistry, Vol. 41, No. 12, 04.06.1998, p. 2134-2145.

Research output: Contribution to journalArticle

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T1 - Substituted naphthofurans as hallucinogenic phenethylamine -Ergoline hybrid molecules with unexpected muscarinic antagonist activity

AU - Monte, Aaron P.

AU - Marona-Lewicka, Danuta

AU - Lewis, Mechelle

AU - Mailman, Richard

AU - Wainscott, David B.

AU - Nelson, David L.

AU - Nichols, David E.

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N2 - 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-HT(2A)/(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 mines 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-HT(2A), 5-HT(2B), and 5-HT(2C) 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- HT(2A) and [3H]-8-OH-DPAT-labeled 5-HT(1A) 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.

AB - 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-HT(2A)/(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 mines 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-HT(2A), 5-HT(2B), and 5-HT(2C) 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- HT(2A) and [3H]-8-OH-DPAT-labeled 5-HT(1A) 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.

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