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At least 19 recordsLinked to original sources
PubMed2006

Dioxane and oxathiane nuclei: suitable substructures for muscarinic agonists.

Muscarinic agonists, bearing 1,4-dioxane and 1,4-oxathiane nuclei, were synthesized and tested to evaluate their potency at M(1)-M(4) muscarinic receptor subtypes. The stereochemical relationship between the 2-side chain and the 6-methyl group plays an important role in drug-receptor interaction, since the cis isomers are more potent than the corresponding trans isomers. However, the latter are able to discriminate between the muscarinic receptor subtypes. Among them compound 5b proves particularly interesting, since it selectively activates the ileal M(3) receptor subtype and is devoid of agonist activity at the others.

Animals↗
PubMed1987

Cross-tolerance between muscarinic agonists: role of muscarinic receptors.

In order to explore the relationship between response to muscarinic agonists and brain muscarinic receptors, two mouse strains that differ in acute sensitivity (DBA and C3H) were injected chronically with DFP or infused with oxotremorine. Chronic DFP-treated DBA mice were not tolerant to DFP's effects on any measure, but they were cross-tolerant to the effects of oxotremorine on heart rate and body temperature. DFP-treated C3H mice were not tolerant to DFP or cross-tolerant to oxotremorine on any measure. Oxotremorine infusion resulted in tolerance to oxotremorine in both mouse strains, and chronically infused DBA mice were cross-tolerant to DFP on five of the six measures. Oxotremorine-infused C3H mice were cross-tolerant to DFP on two of the measures. These results suggest that genetic factors influence the development of tolerance or cross-tolerance. These genetic factors do not seem to be related to changes in brain QNB binding. Both mouse strains showed comparable changes in QNB binding following chronic DFP and oxotremorine with DFP eliciting reductions in QNB binding in striatum and hippocampus and oxotremorine eliciting reductions in nearly every brain region. However, tolerance and cross-tolerance did not seem to correlate with changes in binding which suggests that the relationship between receptor changes and responses to muscarinic agonists must be examined further.

Animals↗
PubMed2001

Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.

Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.

Binding, Competitive↗
PubMed1987

Determination of dissociation constants and relative efficacies of some potent muscarinic agonists at postjunctional muscarinic receptors.

This study was undertaken to determine dissociation constants (KA and relative efficacies (er) of seven muscarinic agonists (methylfurtrethonium; dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) in three isolated tissues (guinea-pig ileum and atria and rat urinary bladder). The rank order of affinities (-log KA) of the various compounds varied depending on the tissue used. er values for the different agonists did not differ significantly from each other in any of the three tissues, except that the er of muscarine in the guinea-pig ileum was higher than those of the other compounds and that of oxotremorine in the rat urinary bladder was lower than those of the other agonists. Comparisons among tissues show that KA and er values were the same in different tissues for some compounds (muscarone, muscarine and methylfurtrethonium), while significant differences were found for the other compounds. This suggests the existence of a discrete receptor population recognized by some but not all agonists. For oxotremorine er as well as -log KA, is greater in atria than in smooth muscle: these factors combine to determine the cardioselectivity of this compound which can now ascribed to receptor selectivity.

Animals↗
PubMed2002

Deoxamuscaroneoxime derivatives as useful muscarinic agonists to explore the muscarinic subsite: demox, a modulator of orthosteric and allosteric sites at cardiac muscarinic M2 receptors.

A series of muscarinic agonists, straight chained, branched, cyclic alkyl and aromatic derivatives of the oxime 1 (demox) was designed with the aim of investigating their activity on muscarinic receptor subtypes. Effects on M1 receptor were assessed functionally by a microphysiometer apparatus, while M2, M3, and M4 receptor potency and affinity were studied on isolated preparations of guinea pig heart, ileum, and lung, respectively. The results suggest that the substitution of a hydrogen with a long side-chain or bulky group generally induces a decrease in potency at M1 and M3 subtypes, while a general increase in this parameter is obtained at M2 subtype. Among the agonists 2-18, compound 4 behaves as a full agonist with a preference for M3 subtype. Moreover, compound 12 is inactive at M1 and M4 receptors while it displays a full agonist activity at M2 and M3 subtypes. Since demox displays a variable response on cardiac M2 receptors regulating heart force, an in-depth inquiry of the functional behaviour of this compound was carried out at M2 receptors. In presence of 10(-11) and 10(-10) M demox, the binding of [3H]-NMS was increased by approximately 30% as a consequence of an increase of the association of [3H]-NMS to membranes; this effect was not observed in presence of a higher concentration of [3H]-NMS. Higher concentrations of demox decreased the binding of [3H]-NMS to heart atrial membranes but significantly retarded the dissociation of this radioligand. Our results suggest that demox may interact with orthosteric and allosteric sites of atrial M2 muscarinic receptor.

Allosteric Regulation↗
PubMed1987

Regional differences in receptor reserve for analogs of oxotremorine in vivo: implications for development of selective muscarinic agonists.

The muscarinic actions of several analogs of oxotremorine were compared in the mouse. Compounds such as AKS 19 and BM 5 having low intrinsic efficacy (partial agonists) differentiated between centrally mediated muscarinic effects as they, like oxotremorine, were potent in producing analgesia and hypothermia but did not produce tremor. Instead they antagonized oxotremorine-induced tremor. They resembled oxotremorine in their ability to stimulate salivary secretion. Excellent correlations were found between the various muscarinic effects measured in vivo and spasmogenic activity on the guinea pig ileum and between tremorolytic potency and affinity for ileal muscarinic receptors. The results suggest that there are regional differences in the receptor reserve for muscarinic agonists that may affect in vivo responses to partial agonists in a qualitative manner. Responses to more efficacious agonists such as oxotremorine are affected only quantitatively by such differences. Efficacious agonists appeared to have a large receptor reserve with respect to salivation, analgesia and hypothermia, whereas their receptor reserve for the tremor response was lower. The possibility is raised of achieving selective muscarinic actions, even in the absence of distinct subtypes of muscarinic receptors, by exploiting regional differences in receptor density, in the efficiency of receptor-effector coupling and in endogenous levels of acetylcholine.

Analgesia↗
PubMed1998

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

3T3 Cells↗
PubMed1993

New functionally selective muscarinic agonists.

The muscarinic pharmacology of two novel agonists related to McN-A-343, 4-F-PyMcN and 4-F-PyMcN+, has been studied by the use of pharmacological and radioligand binding techniques. Both compounds were potent agonists at M1 receptors in rabbit vas deferens (pEC50 = 6.24 and 6.96) and rat duodenum (pEC50 = 5.47 and 6.38), but very weak partial agonists or competitive antagonists at guinea-pig cardiac M2 and ileal M3 receptors. There was no receptor reserve for 4-F-PyMcN in rabbit vas deferens, for which the potency (pEC50 = 6.24) and apparent affinity (pKA = 5.99 and 6.21) were similar. 4-F-PyMcN+ showed only limited binding selectivity between four muscarinic receptor binding assays with apparent affinity constants (pKi) of 5.8, 5.2, 5.6 and 5.7 for M1, M2, M3 and M4 muscarinic receptor subtypes. The two novel functionally M1-selective agonists may provide useful tools with which to study muscarinic receptor mechanisms. The non-quaternary compound, 4-F-PyMcN, might become a starting point for the development of drugs that selectively affect M1 receptors involved in central cholinergic function.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1998

1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.

The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.

Animals↗
PubMed1984

Activation of tyrosine hydroxylase in the superior cervical ganglion by nicotinic and muscarinic agonists.

Both dimethylphenylpiperazinium (DMPP), a nicotinic agonist, and bethanechol, a muscarinic agonist, increase 3,4-dihydroxyphenylalanine (DOPA) synthesis in the superior cervical ganglion of the rat. DMPP causes approximately a fivefold increase in DOPA accumulation in intact ganglia whereas bethanechol causes about a two-fold increase in DOPA accumulation. These effects are additive with each other and with the increase in DOPA accumulation produced by 8-bromo cyclic AMP. The action of DMPP is dependent on extracellular Ca2+ while the actions of bethanechol and 8-bromo cyclic AMP are not dependent on extracellular Ca2+. Cholinergic agonists and cyclic nucleotides produce a stable activation of tyrosine hydroxylase (TH) in the ganglion. The activation of TH by nicotinic and muscarinic agonists can be detected after 5 min of incubation of the ganglia with these agents. The nicotinic response disappears after 30 min of incubation, whereas the muscarinic response persists for at least 30 min. The Ca2+ dependence of the TH activation produced by these agents is similar to the Ca2+ dependence of their effects on DOPA accumulation in intact ganglia. These data are consistent with the hypothesis that nicotinic agonists, muscarinic agonists, and cyclic AMP analogues increase TH activity by three distinct mechanisms. The activation of TH presumably underlies the increase in DOPA synthesis produced by these agents.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1986

Interaction of some muscarinic agonists and antagonists at the prejunctional muscarinic receptor in the rabbit ear artery preparation.

The inhibitory effect of several muscarinic agonists on responses to sympathetic nerve stimulation of the isolated perfused ear artery of the rabbit was compared to that of acetylcholine in preparations pretreated with dyflos, cocaine and yohimbine. In general the potency of the agonists was similar to that observed at peripheral muscarinic sites except for arecaidine propargyl ester and 4-(m-chlorophenylcarbamoyloxy)-2-butynyl trimethylammonium chloride (McN-A-343). The inhibitory effect observed with N-benzyl-3-pyrrolidyl acetate methobromide (AHR-602) was not exerted via muscarinic receptors. With carbachol (CCh) as an agonist, the antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) was found to have a pKB value of 7.74 and thus was 19 fold less active as an antagonist of responses to the agonist, than previously reported for guinea-pig ileum. When McN-A-343 was used as the agonist, the slope of the Schild plot with the antagonist was significantly less than unity. It is suggested that an allosteric interaction of 4-DAMP may be involved with this agonist. By use of an allosteric model, a pKB of 8.56 for 4-DAMP was obtained. Secoverine produced similar pKB values with either CCh (8.19) or McN-A-343 (8.13) as the agonist.

Animals↗
PubMed1984

Pharmacological differences between the high-affinity muscarinic agonist binding states of the rat heart and cerebral cortex labeled with (+)-[3H]cismethyldioxolane.

The high-affinity agonist binding state of muscarinic receptors in the rat heart and cerebral cortex has been pharmacologically characterized in parallel studies. Muscarinic sites were labeled and studied with the aid of a highly specific, rapid filtration binding assay using the potent muscarinic agonist (+)-[3H]CD. Homogenates of both tissues were found to contain a saturable high-affinity (Kd = 1-2 nM), low capacity (6-17% of (-)-[3H]QNB sites) (+)-[3H]CD binding state which demonstrated stereoselectivity and drug specificity typical of a muscarinic site. However, comparative studies of drug potency profiles in competition for myocardial and cerebral cortical (+)-[3H]CD-labeled membranes revealed several major pharmacological differences between muscarinic sites in these tissues. Whereas the muscarinic agonists pilocarpine and McN-A-343, the nonclassical antagonist pirenzepine, and the acetylcholinesterase inhibitor physostigmine reduced (+)-[3H]CD binding in both tissues, their inhibitory effects were more potent (4- to 77-fold) in cerebral cortical membranes. Conversely, gallamine, a nicotinic cholinergic antagonist, demonstrated a 36-fold greater potency at the high-affinity (+)-[3H]CD binding state in myocardial membranes. By comparison, other classical muscarinic agonists and antagonists were nearly equipotent as inhibitors of high-affinity (+)-[3H]CD binding in these two tissues. Thus, these studies for the first time demonstrate that muscarinic receptors in the heart and cerebral cortex can be distinguished pharmacologically by certain drugs which interfere with the high-affinity agonist binding state of the muscarinic recognition site and provide support for the subclassification of these receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1982

Agonist-induced changes in the modulation of K+ permeability and beating rate by muscarinic agonists in cultured heart cells.

The correlation between number of muscarinic cholinergic receptor sites as measured by binding of the muscarinic antagonist [3H]methylscopolamine ([3H]MS) and the ability of muscarinic agonists to mediate a physiologic response was determined in intact heart cells cultured from chick embryos 10 d in ovo. The increase in K+ permeability and the decrease in beating rate mediated by the muscarinic agonist carbamylcholine were the responses studied. Exposure to 10(-3) M carbamylcholine caused a 15% decrease in beating rate and a 33% increase in the rate of 42K+ efflux from cells labeled to equilibrium. An assay for binding of [3H]MS to intact cells was developed. [3H]MS bound specifically to intact heart cells (185 fmol/mg protein) with a Kd of 0.48 nM. Exposure of cells for various times to 10(-3) M carbamylcholine followed by binding of [3H]MS to intact cells demonstrated that a gradual loss of 70% of [3H]MS binding sites took place over the next 6 h with a T 1/2 of 30 min. A decrease in the ability of carbamylcholine to stimulate K+ efflux and to decrease beating rate was observed after pre-exposure of cells to muscarinic agonists. A close correlation was found between the loss of the subclass of muscarinic receptors subject to agonist control and the loss of physiologic responsiveness after agonist exposure. The data suggest the absence of significant numbers of "spare" receptors within this group.

Animals↗
PubMed2007

Short-term exposure to somatostatin or muscarinic agonists reduce acetylcholine-induced 3H-MPP+ release from bovine adrenal medullary cells.

The aim of this work was to investigate the effect of a short-term exposure to somatostatin (SS), its receptors (SSTR) selective agonists as well as muscarinic receptors agonists upon acetylcholine-induced release of (3)H-MPP(+ )from bovine adrenal medullary cells. Acetylcholine (ACH, 100, 500 microM) was found to increase the release of (3)H-MPP(+ )by these cells (to 175 and 171% of basal release, respectively). ACH-elicited (3)H-MPP(+) release was significantly reduced by hexamethonium (100 microM) and atropine (100 microM), selective nicotinic and muscarinic antagonists, respectively. Previous exposure to any of two muscarinic agonists, oxotremorine or pilocarpine, led to a significant reduction of (3)H-MPP(+) release in response to 100 microM ACH, to about a maximum of 51% and 78% of control, respectively. Somatostatin (SS, 0.01-0.1 microM), previously applied to the preparation, depressed ACH-elicited (3)H-MPP(+ )release by 25-27%, but only when a 500 microM ACH concentration was used. The inhibition exerted by SS upon ACH-evoked (3)H-MPP(+) release appeared to be mediated by its SSTR: (1) SSTR2, 3 and 4 subtype agonists mimicked the effects seen with SS, and (2) the SSTR non-selective antagonist, cyclo-SS, counteracted the SS inhibitory effect. When SS was tested in the presence of any of the muscarinic agonists, oxotremorine or pilocarpine, its inhibitory effect on 500 microM ACH-induced (3)H-MPP(+) release was no longer detectable. These results, showing a somewhat similar effect of short-term exposure to SS and muscarinic agonists over ACH-induced release of (3)H-MPP(+), as well as the loss of effect of SS by the presence of the muscarinic agonists, suggest that these compounds may share signalling pathways.

1-Methyl-4-phenylpyridinium↗
PubMed1994

A rapid attenuation of muscarinic agonist stimulated phosphoinositide hydrolysis precedes receptor sequestration in human SH-SY-5Y neuroblastoma cells.

Agonist occupancy of muscarinic cholinergic receptors in human SH-SY-5Y neuroblastoma cells elicited two kinetically distinct phases of phosphoinositide hydrolysis when monitored by either an increased mass of inositol 1,4,5-trisphosphate, or the accumulation of a total inositol phosphate fraction. Within 5s of the addition of the muscarinic agonist, oxotremorine-M, the phosphoinositide pool was hydrolyzed at a maximal rate of 9.5%/min. This initial phase of phosphoinositide hydrolysis was short-lived (t1/2 = 14s) and after 60s of agonist exposure, the rate of inositol lipid breakdown had declined to a steady state level of 3.4%/min which was then maintained for at least 5-10 min. This rapid, but partial, attenuation of muscarinic receptor stimulated phosphoinositide hydrolysis occurred prior to the agonist-induced internalization of muscarinic receptors.

Chemical Fractionation↗
PubMed1987

Influence of atropine and N-methyl atropine pretreatments on behavioral and physiological effects of the irreversible muscarinic agonist, BM123.

The irreversible muscarinic agonist, BM123 (63 mu moles kg-1, IV), was shown to produce central and peripheral physiological signs characteristic of cholinergic agonists. It also induced hypothermia, elevated nociceptive thresholds, reduced locomotor activity and disrupted spontaneous alternation performance in rats. The centrally acting muscarinic antagonist, atropine (50 mu mole kg-1) prevented or reduced all the above effects of BM123 when given SC 40 min prior to the BM123 injection. In contrast, the peripherally acting muscarinic antagonist, N-methyl atropine, prevented only the peripheral effects and the elevated nociceptive thresholds. Habituation of activity during a 20 min session was observed in all groups despite different levels of general activity. These findings are consistent with a model in which atropine and N-methyl atropine compete with BM123 for reversible association with the muscarinic receptor. In the case of BM123 administered alone, the association results, first, in agonist effects and proceeds to form an irreversible complex. Our present results show that by competing with BM123 for mAChR sites during the initial, reversible state of the interaction, atropine blocks the cholinomimetic effects of the agonist during both this state and its otherwise subsequent irreversible state.

Animals↗
PubMed1993

Inhibitory action of muscarinic agonists on neurons in the rat laterodorsal tegmental nucleus in vitro.

1. The effects of the mixed cholinergic agonist carbachol and the muscarinic agonist methacholine (MCh) on neurons of the laterodorsal tegmental nucleus (LDT) were studied with the use of intracellular and whole-cell patch-clamp recordings in a rat brain stem slice preparation. 2. Neurons were classified into one of two categories on the basis of their intrinsic membrane properties: those that displayed a prominent low-threshold calcium burst (LTB, 60%) and those that did not exhibit such a burst (non-LTB, 40%). 3. Neurons from which recordings were obtained were filled with biocytin, visualized with Texas-red avidin, and identified as cholinergic or noncholinergic with NADPH-diaphorase histochemistry. Eighty percent of the LTB neurons that were processed in this manner were cholinergic, and 60% of the non-LTB neurons were cholinergic. 4. Carbachol elicited a membrane hyperpolarization associated with a decrease in input resistance in 95% of the cells tested. Under voltage clamp this response was shown to be due to an outward current that reversed near the equilibrium potential for potassium and displayed marked inward rectification. The conductance/voltage relationship was fit to the Boltzmann equation with a mean V1/2 = -73 +/- 4 (SD) mV and a mean k value of 10 +/- 4. The carbachol-evoked current was fully blocked by extracellular barium. 5. There was no significant effect of carbachol on the transient currents IA or IT. 6. The carbachol-evoked current was mimicked by the specific muscarinic agonist methacholine and blocked by high concentrations of the muscarinic receptor antagonist pirenzepine (IC50 = 580 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗