Detail of "131986-45-3"

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Effects of central muscarinic-1 receptor stimulation on blood pressure regulation

Effects of central muscarinic-1 receptor stimulation on blood pressure regulation. Medina, Aharon; Bodick, Neil; Goldberger, Ary L.; Mac Mahon, Margaret; Lipsitz, Lewis A. (Hebrew Rehabilitation Center Aged Research Training Institute, Harvard Medical School, Boston, MA, USA). Hypertension (Dallas), 29(3), 828-834 (English) 1997 American Heart Association. CODEN: HPRTDN. ISSN: 0194-911X. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 2, 13, 14 Stimulation of central nervous system muscarinic-1 (M1) receptors in animals increases blood pressure, heart rate, and sympathetic outflow. In Alzheimer's disease, stimulation of central M1 receptors is reduced. When the oral formulation of the selective M1 agonist xanomeline was tested for the treatment of Alzheimer's disease, an increased incidence of syncope was obsd. Therefore, we used Alzheimer's disease as a model of relative M1 deficiency to det. the effect of M1 receptor stimulation on blood pressure regulation in humans. Eight Alzheimer's patients and 6 healthy age- and sex-matched subjects underwent blood pressure, heart rate, forearm vascular resistance, plasma norepinephrine, and heart rate variability measurements during 90 min after ingestion of xanomeline or placebo, then during 45 min of head-up tilt. Alzheimer's patients were studied on three occasions: after placebo, the first dose of xanomeline, and 3 days of xanomeline. 131986-45-3 which is the cas registry number is also used here. Normal subjects were studied after placebo and the first dose of xanomeline. A subset of 5 Alzheimer's patients was studied with the peripheral muscarinic antagonist methscopolamine. Oral xanomeline increased supine systolic and diastolic blood pressure in normal subjects and heart rate and plasma norepinephrine in all subjects. During the placebo tilt, 0 of 8 Alzheimer's patients and 2 of 6 healthy subjects developed near-syncope, and during the first-dose xanomeline tilt, 4 of 8 Alzheimer's patients and 3 of 6 healthy subjects had near-syncope. The maximal decrease in systolic blood pressure during tilt was greater with xanomeline than placebo in both groups (P<.03). Methscopolamine did not prevent xanomeline-induced hypotension. Central M1 receptor stimulation with the oral formulation of xanomeline in humans is assocd. with sympathetic stimulation under supine conditions and impaired baroreflex compensation during tilt. Alzheimer's patients, who presumably lack M1 receptor activity, may have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M1 receptor activity is pharmacol. increased. .

Long-term wash-resistant effects of brief interaction of xanomeline at the M1 muscarinic receptor

All Rights Reserved. Long-term wash-resistant effects of brief interaction of xanomeline at the M1 muscarinic receptor. De Lorme, Kayla C.; Sikorski, Krista L.; Grant, Marianne K. O.; El-Fakahany, Esam E. (Division of Neuroscience Research in Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA). Neuroscience Letters, 410(1), 11-14 (English) 2006 Elsevier Ltd. CODEN: NELED5. ISSN: 0304-3940. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Compared to other M1 muscarinic acetylcholine receptor (M1 mAChR) agonists, xanomeline demonstrates both reversible and persistent modes of binding to the receptor. In our study, we investigated the long-term consequences of brief incubation of Chinese hamster ovary cells expressing M1 mAChR (M1-CHO) with low concns. of xanomeline followed by washing off the free drug. Thus, M1-CHO cells were exposed to 100 nM xanomeline for 1 h then washed extensively. Washed cells were either used immediately for binding assays or incubated for 23 h in the absence of free xanomeline. Only the latter treatment conditions resulted in marked attenuation of binding of the muscarinic radioligand [3H]N-methylscopolamine ([3H]NMS) to intact cells. Shortening the xanomeline pretreatment period to 1 min had the same trends as the 1 h pretreatment, implying that xanomeline binds instantly to the receptor to elicit long-term wash-resistant effects. Presence of atropine during the brief period of xanomeline pretreatment did not markedly modulate xanomeline's long-term effects, which suggests that persistent anchoring of the xanomeline mol. to the M1 receptor takes place at a site distinct from the orthosteric binding domain. Our findings suggest the possibility of a time-dependent transition of the conformation of the muscarinic M1 receptor-xanomeline complex between states that vary in their ability to bind [3H]NMS. 131986-45-3 and 51-84-3 are just another two chemicals used in this study. However, possible involvement of other mechanisms of long-term receptor regulation cannot be discounted. .