Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430.
OBJECTIVE
We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine.


METHODS
Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity.


RESULTS
Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430.


CONCLUSIONS
Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors.
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Herman D
HD
Lim
Maristella
M
Adami
Elena
E
Guaita
Thomas
T
Werfel
Rogier A
RA
Smits
Iwan J P
IJ
de Esch
Remko A
RA
Bakker
Ralf
R
Gutzmer
Gabriella
G
Coruzzi
Rob
R
Leurs
D000376:Agmatine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000502:physiology; D005744:Gastric Acid / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D006146:Guanidines; C418607:HRH4 protein, human; D017442:Histamine Agonists; C498829:Hrh4 protein, mouse; C498828:Hrh4 protein, rat; D008761:Methylhistamines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; C025566:4-methylhistamine; D000376:Agmatine; D013890:Thiourea