Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist.
A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods. Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors. Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors. It did not interact with histamine (H1), alpha-1 adrenergic and 5-HT3 receptors in smooth muscle preparations. No inhibition of the uptake of norepinephrine, dopamine or 5-HT was seen. Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action. Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile.
Rinaldi-Carmona
M
M
Sanofi Recherche, Montpellier, France.
Congy
C
C
Santucci
V
V
Simiand
J
J
Gautret
B
B
Neliat
G
G
Labeeuw
B
B
Le Fur
G
G
Soubrie
P
P
Breliere
J C
JC
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004569:Electroencephalography; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects
D005464:Fluorobenzenes; D010636:Phenols; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C076033:SR 46349B; D007650:Ketanserin