title: N(G)-acylated aminothiazolylpropylguanidines as potent and selective histamine H(2) receptor agonists.
abstract: The bioisosteric replacement of the guanidino group in arpromidine-like histamine H(2) receptor (H(2)R) agonists by an acylguanidine moiety is a useful approach to obtain potent H(2)R agonists with improved oral bioavailability and blood-brain barrier penetration. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropylguanidines for the H(2)R is poor, in particular versus histamine H(3) (H(3)R) and H(4) receptors (H(4)R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H(2)R-selective histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H(2)R agonists. The aminothiazoles are nearly equipotent to the corresponding imidazoles as H(2)R agonists. Compared with histamine, the potency is increased up to 40-fold on the guinea pig right atrium, and up to 125- and 280-fold in GTPase assays with human and guinea pig H(2)R-G(salphaS) fusion proteins expressed in Sf9 insect cells, respectively. Docking studies on H(2)R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H(2)Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H(1), H(3), and H(4) receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H(2)R agonism of N(G)-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kraus
authors.forename: Prasanta
authors.initials: P
authors.lastname: Ghorai
authors.forename: Tobias
authors.initials: T
authors.lastname: Birnkammer
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000215:Acylation; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D017442:Histamine Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D018411:Spodoptera
chemical_list: D006146:Guanidines; D017442:Histamine Agonists; D011970:Receptors, Histamine H2; D020558:GTP Phosphohydrolases