New functionally selective muscarinic agonists

Lambrecht, Günter; Moser, Ulrich; Grimm, Ulrike; Pfaff, Otmar; Hermanni, Ulrike; Hildebrandt, Caren; Waelbroeck, Magalì; Christophe, Jean; Mutschler, E.

doi:10.1016/0024-3205(93)90305-m

Cited by 40 publications

(12 citation statements)

References 12 publications

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“…The studies on inhibition of adenylate cyclase activity in myocardial homogenates included those of Ehlert (1985), Keen and Nahorski (1988) and Ehlert et al (1996). The studies on the isolated, guinea-pig, left atrium were from Christopoulos and Michelson (1997) and Lambrecht et al, (1993). RA i values for the M 3 receptor were estimated from studies measuring contraction in the guinea-pig ileum and phosphoinositide hydrolysis in cells and tissues.…”

Section: Resultsmentioning

confidence: 99%

“…We have found that agonists typically exhibit Hill slopes close to one in these types of experiments, suggesting that the simple calculation was valid in these instances. In the remaining two cases (R-aceclidine in the rabbit vas deferens (Eltze et al, 1993 and McN-A-343 in guinea pig right atrium, Lambrecht et al, 1993), the E max values of the agonists were 86 and 59% of the standard agonist, respectively. We expect the simple calculation of RA i to be valid in the case of R-aceclidine because its E max is close to 100%.…”

Section: Methodsmentioning

confidence: 99%

“…The estimates were calculated from the published concentration-response curves of Lazareno et al (1993), Eltze et al (1993), Mei et al (1991), Richard and Giersbergen (1995), Schwarz et al (1993), Griffin et al (2007), Ehlert (1985), McKinney et al (1991), Ehlert et al (1996), Keen and Nahorski (1998), Christopoulos and Mitchelson (1993), Ehlert et al (1999), Matsumoto et al (1994), Ek and Nahorski (1998), Hanin (1966) and Ringdahl et al (1982), Wang and El-Fakahany (1993) and Lambrecht et al (1993). Asterisks are used to indicate the RA i values estimated from the study of Eltze et al (1993) on the rabbit vas deferens because there is a question as to whether this response is M 1 as indicated in the figure or M 4 .…”

Section: Figures and Tablesmentioning

confidence: 99%

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Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes

Figueroa

Griffin²,

Ehlert³

2008

J Pharmacol Exp Ther

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We measured the intrinsic relative activity (RA i ) of muscarinic agonists to detect possible selectivity for receptor subtypes and signaling pathways. RA i is a relative measure of the microscopic affinity constant of an agonist for the active state of a GPCR expressed relative to that of a standard agonist. Our results show that the RA i estimate is a useful receptordependent measure of agonist activity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Figures and Tablesmentioning

confidence: 99%

See 1 more Smart Citation

Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes

Figueroa

Griffin²,

Ehlert³

2008

J Pharmacol Exp Ther

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“…Based on our results obtained in RAM and on the caveats cited above, it is not possible to clearly define the subtype of muscarinic receptor mediating contraction in RAM using the agonist approach. However, the very weak partial agonism of the M 1 -selective agonists McN-A-343 and 4-Cl-McN-A-343 (Eltze et al 1993;Lambrecht et al 1993) might, with accepted limitations, exclude the M 1 subtype for mediating the contraction in RAM. More definitive are subtype-preferring antagonists ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Weiser

Mutschler

Lambrecht

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The present study was designed to characterize the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle by means of a series of muscarinic agonists and subtype-preferring key muscarinic antagonists. Cumulative addition of muscarinic agonists elicited concentration-dependent contractions with the following rank order of potency (pD2 values): (+)-muscarine (6.36) > or = oxotremorine M (6.21) > or = arecaidine propargyl ester (APE) (6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > 4-(4-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) > 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine were competitively antagonized by pirenzepine (pA2 = 6.92), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b) (1,4)-benzodiazepine-6-one (AQ-RA 741; pA2 = 6.75), himbacine (pA2 = 7.11), (+/-)-p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2 = 7.68) and the (R)- and (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA2 = 8.52; (S)-HHD: pA2 = 6.06]. A comparison of the pA2 values derived from studies of contraction in rat anococcygeus muscle with literature binding (pKi values) and functional affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle are of the M3 subtype.

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“…For some agonists investigated in the present study a functional selectivity for M 1 and/or M 4 over M 2 and M 3 receptors has been reported: McN-A-343 was shown to be a selective muscarinic agonist at native M 1 receptors in rabbit vas deferens and rat duodenum (Lambrecht et al 1993) but m4-selective at human recombinant receptors (Richards and van Giersbergen 1995). (S)-BN 228, the eutomer of the stereoisomers of BN 228, is a potent and functionally selective M 1 agonist exhibiting a 10-fold higher activity at M 1 receptors than McN-A-343 .…”

Section: Characterization Of Muscarinic Receptors Mediating Nanc Relamentioning

confidence: 99%

Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle

Gross

Mutschler

Lambrecht

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of the present study was to characterize the muscarinic receptor subtype mediating nonadrenergic noncholinergic (NANC) relaxations in the rabbit anococcygeus muscle (RAM) by the use of muscarinic receptor agonists and a battery of key muscarinic antagonists. In addition, experiments were carried out to identify the NANC neurotransmitter(s) involved in the inhibitory NANC neurotransmission. In preparations with histamine-raised tone, the nonselective muscarinic agonists (pD2 values) (+)-muscarine (5.23), cis-dioxolane (5.16), oxotremorine M (4.95) and carbachol (4.06) produced concentration-dependent relaxations corresponding to 72.6-85.0% of the histamine-induced precontraction. In contrast, the subtype-preferring (M1/M4 over M2 and M3 receptors) agonists 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343), (S)-4-(dimethylamino)-1-methyl-2-butynyl-N-(3-chlorophenyl)carbamate methobromide [(S)-BN 228], (R)- and (S)-N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide [(R)- and (S)-BM 5] showed no or rather low [(S)-BN 228] muscarinic activity. The low potencies, together with the ineffectiveness of some agonists, indicated a low effective receptor reserve associated with the relaxant response. No contractile responses to (+)-muscarine were observed neither in unstimulated nor in precontracted preparations suggesting that the existence of an excitatory postjunctional muscarinic receptor may be excluded. The nicotinic antagonist hexamethonium had no influence on relaxant responses to (+)-muscarine, but abolished relaxations elicited by (-)-nicotine. This demonstrates that the RAM contains also nicotinic acetylcholine receptors (AchRs) mediating inhibitory NANC responses. Relaxations induced by the stimulation of muscarinic and nicotinic AchRs as well as by electrical field stimulation (EFS) were completely abolished by tetrodotoxin and were also sensitive to the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG), indicating that NO plays an important role as an inhibitory NANC transmitter in RAM. All muscarinic antagonists investigated did not influence the histamine-induced precontraction, but shifted the concentration-response curve of (+)-muscarine to the right in a parallel fashion. Schild analysis yielded regression lines of unit slope, indicating competitive antagonism. The following rank order of antagonist potencies (pA2 values) was found: 11-([4-[4-(diethylamino)-butyl]-1-piperidinyl]-acetyl-5,11-dihydro-6H-py rido (2,3-b) (1,4)-benzodiazepine-6-one hydrochloride (AQ-RA 741; 8.08) = himbacine (8.03) > or = tripitramine (7.69) > or = p-fluorohexahydro-sila-difenidol (p-F-HHSiD; 7.48) > or = methoctramine (7.30) > or = pirenzepine (7.18) > or = guanylpirenzepine (6.24). A comparison of the pA2 values determined in the RAM with published data from binding studies at muscarinic M1-M4 and m5 receptors suggests that the functional muscarinic receptor mediating NANC relaxation in the RAM is of the M4 subtype. Taken together, the results obtained in the present...

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New functionally selective muscarinic agonists

Cited by 40 publications

References 12 publications

Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes

Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle

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New functionally selective muscarinic agonists

Cited by 40 publications

References 12 publications

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle

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Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes

Selectivity of Agonists for the Active State of M₁ to M₄ Muscarinic Receptor Subtypes