Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity

• Published in: Journal of medicinal chemistry Vol. 41; no. 12; pp. 2134 - 2145
• Main Authors: Monte, Aaron P, Marona-Lewicka, Danuta, Lewis, Mechelle M, Mailman, Richard B, Wainscott, David B, Nelson, David L, Nichols, David E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.06.1998; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Cell Line; Chemistry, Medicinal; Cholinergic system; Cricetinae; Discrimination Learning - drug effects; Ergolines - chemistry; Furans - chemical synthesis; Furans - chemistry; Furans - metabolism; Furans - pharmacology; Hallucinogens - chemical synthesis; Hallucinogens - chemistry; Hallucinogens - metabolism; Hallucinogens - pharmacology; Humans; Life Sciences & Biomedicine; Lysergic Acid Diethylamide - pharmacology; Male; Medical sciences; Mice; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - chemistry; Muscarinic Antagonists - metabolism; Muscarinic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenethylamines - chemistry; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic - metabolism; Receptors, Serotonin - metabolism; Recombinant Proteins - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacology; DRUG DISCRIMINATION; 5-HT2 RECEPTOR; TRYPTAMINES; 5-HYDROXYTRYPTAMINE2 RECEPTOR; BEHAVIORAL ACTIVITY; PHARMACOLOGY; SPECIES-DIFFERENCES; POLYMERASE CHAIN-REACTION; SITE-DIRECTED MUTAGENESIS; BINDING; Human; Rodentia; Tricyclic compound; Oxygen heterocycle; In vitro; Stereoselectivity; Vertebrata; Cholinergic receptor; Mammalia; Structure activity relation; Mouse; Animal; Racemate; Affinity; Bromine Organic compounds; Aromatic compound; Muscarinic receptor; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980076u

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.