title: N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues.
abstract: A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca(2+) mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.
authors.affiliation: †Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.affiliation: †Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors.forename: M Flori
authors.initials: MF
authors.lastname: Sassano
authors.forename: Adam L
authors.initials: AL
authors.lastname: Halberstadt
authors.forename: Landon M
authors.initials: LM
authors.lastname: Klein
authors.affiliation: ∥School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, U.K.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
authors.affiliation: ⊥ROAR Forensics, Malvern Hills Science Park, Geraldine Road, Malvern, Worcestershire WR14 3SZ, U.K.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Elliott
authors.affiliation: #Hurststrasse 6a, D-69514 Laudenbach, Germany.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Fiedler
mesh_terms: D008735:5-Methoxytryptamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D019416:Head Movements / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D014363:Tryptamines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010627:Phenethylamines; D011985:Receptors, Serotonin; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D014363:Tryptamines; C006731:N-benzyl-5-methoxytryptamine; D008735:5-Methoxytryptamine
keywords: 5-HT2 receptors; 5-HT2A; 5-methoxytryptamine; Serotonin; agonist; mouse head twitch; phenethylamine