Synthesis and Serotonin Receptor Affinities of a Series of trans-2-(Indol-3-yl)cyclopropylamine Derivatives

• Published in: Journal of medicinal chemistry Vol. 41; no. 25; pp. 4995 - 5001
• Main Authors: Vangveravong, Suwanna, Kanthasamy, Arthi, Lucaites, Virginia L, Nelson, David L, Nichols, David E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.12.1998; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Cell Line; Chemistry, Medicinal; Cricetinae; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - metabolism; Humans; In Vitro Techniques; Indoles - chemical synthesis; Indoles - chemistry; Indoles - metabolism; Life Sciences & Biomedicine; Medical sciences; Mesocricetus; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Recombinant Proteins - metabolism; Science & Technology; Serotoninergic system; Stereoisomerism; INHIBITION; TRYPTAMINE ANALOGS; RAT FRONTAL-CORTEX; PHARMACOLOGY; ENANTIOMERS; BINDING; AGONISTS; Human; Cyclopropane derivatives; Rat; Ligand; Rodentia; Central nervous system; In vitro; 5-HT2 Serotonine receptor; Racemic; Vertebrata; Biological fixation; Mammalia; 5-HT1A Serotonine receptor; Structure activity relation; Animal; Trans stereoisomer; Affinity; Indole derivatives; Chemical synthesis; Primary amine; Brain (vertebrata)
• DOI: 10.1021/jm980318q
• ISSN: 0022-2623

A series of four racemic ring-substituted trans-2-(indol-3-yl)cyclopropylamine derivatives was synthesized and tested for affinity at the 5-HT1A receptor, by competition with [3H]-8-OH-DPAT in rat hippocampal homogenates, and for affinity at the agonist-labeled cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. None of the compounds had high affinity for the 5-HT1A receptor, with the 5-methoxy substitution being most potent (40 nM). At the 5-HT2A and 5-HT2B receptor isoforms, most of the compounds lacked high affinity. At the 5-HT2C receptor, however, affinities were considerably higher. The 5-fluoro-substituted compound was most potent, with a K i at the 5-HT2C receptor of 1.9 nM. In addition, the 1R,2S-(−) and 1S,2R-(+) enantiomers of the unsubstituted compound were also evaluated at the 5-HT2 isoforms. While the 1R,2S enantiomer had higher affinity at the 5-HT2A and 5-HT2B sites, the 1S,2R isomer had highest affinity at the 5-HT2C receptor. This reversal of stereoselectivity may offer leads to the development of a selective 5-HT2C receptor agonist. The cyclopropylamine moiety therefore appears to be a good strategy for rigidification of the ethylamine side chain only for tryptamines that bind to the 5-HT2C receptor isoform.