Detail of "40796-97-2"

Reference

Effects of the antagonists MDL 72222 and ketanserin on responses of cat carotid body chemoreceptors to 5-hydroxytryptamine

Effects of the antagonists MDL 72222 and ketanserin on responses of cat carotid body chemoreceptors to 5-hydroxytryptamine. Kirby, G. C.; McQueen, D. S. (Med. Sch., Univ. Edinburgh, Edinburgh EH8 9JZ, UK). Br. J. Pharmacol., 83(1), 259-69 (English) 1984. CODEN: BJPCBM. ISSN: 0007-1188. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) Section cross-reference(s): 1 The effects of intracarotid (i.c.) injections of 5-hydroxytryptamine (5-HT) [50-67-9](1-50 mg) on carotid chemoreceptor activity recorded from the carotid sinus nerve were studied in anesthetized cats. A transient burst of activity was obtained during the injection period in 56% of the recordings. In all the recordings a period of chemodepression commenced a few seconds after completing the injection and was usually dose related. A delayed longer-lasting chemoexcitation occurred in many expts., concomitant with a fall in systemic blood pressure. The neuronal 5-HT receptor antagonist MDL 72222 [40796-97-2] (10-100 mg/kg, i.c.) virtually abolished the transient chemoexcitation evoked during 5-HT injections and also increased the mean ID50 for 5-HT-induced chemodepression. Neither the delayed chemoexcitation nor the hypotension caused by 5-HT were much affected by the antagonist. MDL 72222 itself had a biphasic effect on chemosensory discharge, causing depression followed by a delayed excitation. The 5-HT2-receptor antagonist ketanserin [74050-98-9] (100 mg/kg, i.c.) had no appreciable effect on the transient chemoexcitation evoked during 5-HT injections and caused a slight but significant increase in the mean ID50 for 5-HT-induced chemodepression. The delayed chemoexcitation and accompanying hypotension assocd. with 5-HT were both substantially reduced or abolished by the antagonist. Ketanserin itself caused a short-lasting period of chemoexcitation. All the effects of injected 5-HT on chemosensory discharge were abolished by the combination of MDL 72222 and ketanserin. Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia. At least 2 types of 5-HT receptor appeared to be involved in the response of carotid body chemoreceptors to 5-HT. Transient excitation and chemodepression were mediated via MDL 72222-sensitive (peripheral neuronal) receptors whereas the delayed chemoexcitation and assocd. hypotension involved a ketanserin-sensitive, presumably 5-HT2, receptor. It appears unlikely that 5-HT plays a crucial role in chemoreception.

MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors

MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Fozard, J. R. (Strasbourg Cent., Merrell Dow Res. Inst., Strasbourg F-67084, Fr.). Naunyn-Schmiedeberg's Arch. Pharmacol., 326(1), 36-44 (English) 1984. CODEN: NSAPCC. ISSN: 0028-1298. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 2 The properties of MDL 72222 (1aH,3a,5aH-tropan-3-yl-3,5-dichlorobenzoate (I) [40796-97-2] are described. I was a potent antagonist of responses mediated through the receptors for 5-HT [50-67-9] present on the terminal sympathetic fibers of isolated rabbit heart. I was also highly selective since responses to the nicotine receptor agonist, DMPP [54-77-3], were inhibited only at concns. >1000 times those necessary to inhibit 5-HT. In the anesthetized rat, I produced marked blockade of the Bezold-Jarisch effect of 5-HT. Again, inhibition was selective since much higher doses of I failed to alter the response to elec. stimulation of the efferent vagus nerves. In contrast, I proved only a weak and essentially nonselective antagonist of responses mediated by the 5-HT M-receptor present on the cholinergic nerves of the guinea pig ileum. I does not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholinoceptors, or histamine H1-receptors, except at relatively high concns. Similarly, in a no. of radioligand binding assays carried out using brain tissue membranes, the displacing effects of I were absent or weak at sites identifying compds. with activity at a1, a2, or b-adrenoceptors, 5-HT1 or 5-HT2 receptors, benzodiazepine receptors, or histamine H1-receptors. I is the 1st reported selective and potent antagonist of responses mediated through the 5-HT receptors present on the terminal sympathetic neurons of the rabbit heart and on the neurons subserving the afferent limb of the Bezold-Jarisch reflex. The compd. should provide a useful means by which responses mediated through such sites can be distinguished.