Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine.
Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.
De Esch
I J
IJ
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Vollinga
R C
RC
Goubitz
K
K
Schenk
H
H
Appelberg
U
U
Hacksell
U
U
Lemstra
S
S
Zuiderveld
O P
OP
Hoffmann
M
M
Leurs
R
R
Menge
W M
WM
Timmerman
H
H
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D017442:Histamine Agonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C118867:VUF 5296; D006632:Histamine; D009638:Norepinephrine