In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist mizolastine with H1 receptors in the rodent.
The interaction of mizolastine (CAS 108612-45-9, SL 85.0324) with histamine H1 receptors has been evaluated in the rodent. Mizolastine inhibited with high affinity (IC50 = 47 nmol/l) the binding of [3H]pyrilamine to histamine H1 receptors in guinea pig cerebellar membranes and sections. The order of potency of mizolastine and various H1 antagonists in this binding assay was the following: cyproheptadine > pyrilamine > mequitazine > mizolastine > astemizole > terfenadine > cetirizine > loratadine. Mizolastine also potently antagonized the contractile effects of histamine in the guinea pig ileum (pA2 = 8.5) and histamine-induced stimulation of phosphoinositide turnover in rat cortical slices (IC50 = 0.35 mumol/l). In contrast, this compound displayed very low affinity for serotonergic, noradrenergic and muscarinic cholinergic receptors as evidenced in both binding assays and functional tests. In guinea pig cerebellar membranes, [3H]mizolastine labelled in a saturable and reversible manner a single population of binding sites with Kd and Bmax values of 1.1 nmol/l and 635 fmol/mg protein, respectively. [3H]Mizolastine binding in guinea pig cerebellar membranes was inhibited by histamine (IC50 = 30 mumol/l) and by drugs that possess affinity for the H1 receptor such as pyrilamine (IC50 = 1 nmol/1), DL-chlorphenyramine (IC50 = 6.4 nmol/l) terfenadine (IC50 = 6 nmol/l) and loratadine (IC50 = 50 nmol/l). At concentrations lower than 10 mumol/l, the H2 receptor ligands dimaprit and cimetidine and the H3 receptor ligands burimamide and 4-methyl-histamine failed to displace [3H]mizolastine binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Benavides
J
J
Synthélabo Recherche, Central Nervous System Department, Bagneux, France.
Schoemaker
H
H
Dana
C
C
Claustre
Y
Y
Delahaye
M
M
Prouteau
M
M
Manoury
P
P
Allen
J
J
Scatton
B
B
Langer
S Z
SZ
D000818:Animals; D001345:Autoradiography; D001562:Benzimidazoles / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D011738:Pyrilamine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; D010716:Phosphatidylinositols; D011969:Receptors, Histamine H1; D017981:Receptors, Neurotransmitter; C076170:mizolastine; D006632:Histamine; D011738:Pyrilamine