Synthesis and serotonin receptor affinities of a series of trans-2-(indol-3-yl)cyclopropylamine derivatives.
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 Ki 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.
Vangveravong
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S
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Kanthasamy
A
A
Lucaites
V L
VL
Nelson
D L
DL
Nichols
D E
DE
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008647:Mesocricetus; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
D003521:Cyclopropanes; D007211:Indoles; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins