Effects of iodoproxyfan, a potent and selective histamine H3 receptor antagonist, on alpha 2 and 5-HT3 receptors.
We determined the affinity and/or potency of the novel H3 receptor antagonist iodoproxyfan at alpha 2 and 5-HT3 receptors. Iodoproxyfan and rauwolscine (a reference alpha 2 ligand) (i) monophasically displaced 3H-rauwolscine binding to rat brain cortex membranes (pKi 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with 3H-noradrenaline (pEC50 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA2 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mumol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD'2 5.24). Tropisetron (a reference 5-HT3 antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA2 7.84). In conclusion, the affinity/potency of iodoproxyfan at H3 receptors (range 8.3-9.7 [1]) exceeds that at alpha 2 receptors by at least 1.5 log units and that at 5-HT3 receptors by at least 3 log units.
Schlicker
E
E
Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany.
Pertz
H
H
Bitschnau
H
H
Purand
K
K
Kathmann
M
M
Elz
S
S
Schunack
W
W
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D012015:Reference Standards; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D000077526:Tropisetron; D015016:Yohimbine / Q000378:metabolism
D006635:Histamine H2 Antagonists; D007093:Imidazoles; D007211:Indoles; D007457:Iodine Radioisotopes; D018341:Receptors, Adrenergic, alpha-2; D018100:Receptors, Histamine H3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090115:iodoproxyfan; D015016:Yohimbine; D012701:Serotonin; D000077526:Tropisetron; D009638:Norepinephrine