Characterization of muscarinic agonists in recombinant cell lines

Schwarz, Roy D.; Davis, Robert E.; Jaén, Juan C.; Spencer, Carolyn J.; Tecle, Haile; Thomas, Anthony J.

doi:10.1016/0024-3205(93)90303-k

Cited by 39 publications

(33 citation statements)

References 11 publications

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“…Other contradictory results observed with muscarinic receptors expressed in CHO cells include a report by Schwarz et al (1993) that PI turnover is more sensitive to muscarinic agonists than the cyclic AMP assay, clearly different from the data of Lazareno et al (1993), Wang & El-Fakahany (1993) and the present results. Although the cloned muscarinic receptors used in three of these studies are from the same source, there are differences in receptor gene expression, receptor-effector coupling efficiencies and agonist activation of these receptors.…”

Section: Experiments With Propylbenzilylcholine Mustardcontrasting

confidence: 57%

“…In contrast, cloned ml and m3 receptors were more resistant to propylbenzilylcholine mustard, requiring 200 nM of the alkylating agent to decrease the maximum response to carbachol in CHO cells expressing low receptor densities (B. < 300 fmol binding sites mg-' protein; Hu & ElFakahany, 1990) and 10 gM propylbenzilylcholine mustard in cells expressing moderate (this paper) or high receptor densities (B.,= 2900 fmol mg' protein; Schwarz et al, 1993 (8,4,-) RS 86 (8,3,-) 1 pmol mg-' protein (Yasuda et al, 1993;see Table 1 for density of CHOm4 receptors). All agonists were more potent in inhibiting cyclic AMP formation in CHOm4 cells than in rat striatum.…”

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 75%

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 87%

“…Carbachol did not distinguish between CHOm1 and CHOm3 receptors in membrane preparations (Results) or intact cells (Hu & El-Fakahany, 1990;Schwarz et al, 1993). However, Hu & El-Fakahany (1990) (Table 2) whereas in intact cells differences among (fewer) agonists were six fold or less (Schwarz et al, 1993). Slopes and affinities of agonists binding to muscarinic receptors that inhibit adenylyl cyclase are more readily modulated by changes in the ionic strength of the buffer and the presence or absence of GTP than are muscarinic receptors linked to phosphatidylinositol turnover (references cited in Richards, 1991).…”

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 94%

“…The dissociation constants of some partial agonists (Table 5) (Richards, 1990) and binding studies (Nivelbrant & Sparf, 1986) and that estimates of muscarinic antagonist affinity values at a given receptor subtype may vary by three fold or more (Mitchelson, 1988;Caulfield, 1993 (Baumgold & White, 1989, membranes prepared in physiological buffer) whereas no difference was observed in intact CHO cells (Schwarz et al, 1993). Carbachol did not distinguish between CHOm1 and CHOm3 receptors in membrane preparations (Results) or intact cells (Hu & El-Fakahany, 1990;Schwarz et al, 1993).…”

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 99%

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Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Richards¹,

Giersbergen²

1995

British J Pharmacology

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Section: Experiments With Propylbenzilylcholine Mustardcontrasting

confidence: 57%

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 75%

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 87%

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 94%

Section: Experiments With Propylbenzilylcholine Mustardmentioning

confidence: 99%

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Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Richards¹,

Giersbergen²

1995

British J Pharmacology

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Development of M1 subtype selective muscarinic agonists for Alzheimer's disease: Translation of in vitro selectivity into in vivo efficacy

Schwarz¹,

Callahan²,

Davis³

et al. 1997

Drug Dev. Res.

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Clinical trials in Alzheimer's disease (AD) with first generation muscarinic agonists (e.g., arecoline, oxotremorine, pilocarpine) produced inconsistent results due to poor pharmacokinetic properties and a lack of separation between central and peripheral activities observed with these compounds. Second generation agonists have sought to optimize physicochemical properties, and in most cases, target specific subtypes of muscarinic receptor to overcome these limitations. Based upon receptor distribution in both central and peripheral nervous systems, agonists of the m1/M1 subtype seem to possess the desired profile for AD treatment. For the discovery and characterization of these selective agents, the use of clonal cell lines expressing the five subtypes of muscarinic receptors (m1–m5) has become pivotal. However, their use is not without limitations. Results from functional assays (e.g., activation of second messengers) reliably measures subtype selectivity, whereas receptor binding underestimates selectivity. From a novel series of azabicyclic oximes, PD151832 has been chosen for further development and data obtained with this M1 muscarinic agonist is used to exemplify central and peripheral animal models of cholinergic activity and the ability to translate in vitro subtype selectivity into in vivo efficacy. Drug Dev. Res. 40:133–143, 1997. © 1997 Wiley‐Liss, Inc.

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Xanomeline: A selective muscarinic agonist for the treatment of Alzheimer's disease

et al. 1997

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Xanomeline is a novel muscarinic receptor agonist relatively devoid of parasympathomimetic side effects. Xanomeline had high affinity for muscarinic receptors and much lower affinity for a variety of other neuronal receptors in radioligand binding assays. Functional studies in cell lines transfected with the muscarinic receptor subtypes demonstrated that xanomeline had higher potency and efficacy for m1 and m4 receptors than m2, m3, and m5 receptor subtypes. Similarly, in isolated tissue studies, xanomeline had higher potency and efficacy for M1 receptors in rabbit vas deferens than at M2 receptors in guinea pig atria or M3 receptors in guinea pig bladder. Secretion of soluble amyloid precursor protein from m1 cell lines was potently stimulated by xanomeline. In vivo, xanomeline robustly stimulated phosphoinositide hydrolysis in brain, consistent with m1 agonism. Xanomeline produced modest increases in brain acetylcholine levels and did not produce bradycardia, suggesting little, if any, m2 agonist activity in vivo. Additionally, xanomeline did not induce nonselective cholinergic agonist side effects such as tremor, hypothermia and salivation. In animal behavior studies, xanomeline reduced locomotion and blocked memory deficits that were induced by a muscarinic antagonist in a passive avoidance paradigm. Xanomeline was found to be safe and reasonably well tolerated in safety studies in humans. In a placebo controlled double blind clinical trial of 6 months duration, xanomeline halted cognitive decline in patients with Alzheimer's disease. Furthermore, behavioral symptoms associated with Alzheimer's disease such as hallucinations, delusions and vocal outbursts were significantly decreased by xanomeline treatment. Additional clinical trials are under way to assess the novel therapeutic effects of xanomeline. Drug Dev. Res. 40:158–170, 1997. © 1997 Wiley‐Liss, Inc.

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Characterization of muscarinic agonists in recombinant cell lines

Cited by 39 publications

References 11 publications

Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists

Development of M1 subtype selective muscarinic agonists for Alzheimer's disease: Translation of in vitro selectivity into in vivo efficacy

Xanomeline: A selective muscarinic agonist for the treatment of Alzheimer's disease

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