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At least 37 records · Page 2Linked to original sources
PubMed1984

Desensitization of membrane-bound Torpedo acetylcholine receptor by amine noncompetitive antagonists and aliphatic alcohols: studies of [3H]acetylcholine binding and 22Na+ ion fluxes.

Measurements of the kinetics of binding of [3H]acetylcholine ([3H]AcCh) to membrane-bound nicotinic AcCh receptors from Torpedo electric tissue have been used to characterize the effects of a series of amine and alcohol noncompetitive antagonists on receptor conformational equilibria. The receptor exists in multiple, interconvertible conformations distinguished by agonist binding affinity. In the absence of cholinergic ligands, certain aromatic amines including proadifen, dimethisoquin, and lidocaine, as well as propanol and butanol, produce a dose-dependent increase in the fraction of receptors (f) in a high-affinity conformation from a value of fmax approximately 0.17 in the absence of drug to fmax approximately 0.9. Not all noncompetitive antagonists produce that same value of fmax. For histrionicotoxin (HTX), fmax approximately 0.3, and the aromatic amine adiphenine did not alter f while tetracaine actually decreased f to 0.1. The high-affinity receptor conformation stabilized by noncompetitive antagonists was characterized by (1) the rate constant (krec) for receptor reisomerization upon removal of stabilizing ligand and (2) the rate constant (kdis) for dissociation of [3H]AcCh-receptor complexes. On the basis of these criteria, the high-affinity receptor conformation stabilized by amine and alcohol noncompetitive blockers is the same as that stabilized by agonist. At 4 degrees C, krec = (2.2 +/- 0.2) X 10(-3) s-1 and kdis = 4 X 10(-2) s-1. Since HTX and adiphenine produced only a small conformational perturbation, their effects on the actions of proadifen and 2-propanol were examined. HTX and adiphenine antagonized the conformational perturbation caused by proadifen, while mixtures of HTX and 2-propanol produced additive effects. Effects of noncompetitive blockers were also assayed in terms of the inhibition of agonist-induced efflux of 22Na+ from Torpedo vesicles. Exposure to proadifen in the absence of agonist produced a reversible inhibition (desensitization) of the flux response, and recovery from desensitization occurred at the same rate as the reisomerization from the high-affinity receptor state.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1987

Comparison of in vitro actions with behavioral effects of antimuscarinic agents.

In vitro potencies of a series of muscarinic antagonists were compared with their effects on operant behavior. Ki values for inhibition of [3H]N-methylscopolamine binding in N4TG1 neuroblastoma cells correlated positively with ED50 values for the inhibition of carbachol-induced alpha-amylase release from pancreatic acini cells and with KB values for inhibition of acetylcholine-induced contractions of guinea pig ileum. The rank order of potency for inhibition of [3H]N-methylscopolamine binding was quinuclidinyl benzilate = quinuclidinyl xanthene-9-carboxylate greater than (methyl atropine = atropine) greater than benactyzine greater than azaprophen greater than (adiphenine = aprophen) greater than pirenzepine greater than ethyl aprophen. The M1 antagonist, pirenzepine, was a weak inhibitor in the guinea pig ileum and alpha-amylase assays relative to its ability to inhibit [3H]N-methylscopolamine binding; azaprophen exhibited the opposite relationship. Lever-press responses of rats were maintained by food delivery under a schedule requiring 10 responses for each food presentation. The high response rates engendered by this schedule were decreased in a dose-dependent manner by all compounds. The order of potency for this behavioral effect (ED50) was atropine = azaprophen greater than aprophen greater than (methyl atropine = benactyzine) greater than pirenzepine greater than adiphenine. Behavioral depressant actions of the antimuscarinics correlated positively with their potencies in inhibiting alpha-amylase secretion. Pirenzepine was unique in being relatively more potent in its behavioral effects than in its actions in vitro. In contrast to the other antimuscarinic agents studied, the benzilates, benactyzine, aprophen and adiphenine, but not azaprophen, increased behavioral response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Muscarinic receptor subtype mediating vasodilation feline middle cerebral artery exhibits M3 pharmacology.

The nature of the muscarinic receptor subtype mediating the endothelium-dependent relaxation of the cat middle cerebral artery was investigated in vitro by recording the smooth muscle isometric tension of precontracted arterial segments. Relaxation induced by several agonists (acetylcholine (ACh), acetyl-beta-methylcholine, oxotremorine, carbachol and McN-A-343) was recorded. The ability of selective (pirenzepine, dicyclomine, adiphenine, AF-DX 116, methoctramine, gallamine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and hexahydro-sila-difenidol (HHSiD] and non-selective antagonists (atropine, scopolamine and quinuclidinyl benzilate (QNB] to block the relaxation induced by ACh was also estimated. The weak activity of the poorly selective M1 muscarinic receptor as together with the intermediate affinity of pirenzepine and adiphenine tend to exclude the M1 muscarinic receptor as the primary mediator of the cholinergic relaxation. The low affinity of AF-DX 116 and methoctramine further suggested that the cerebrovascular muscarinic receptor does not correspond to the M2 cardiac subtype. In contrast, 4-DAMP and HHSiD potently inhibited the ACh-induced relaxation with affinities similar to those reported at the M3 glandular receptor. We conclude that a similar to the pharmacological M3 muscarinic receptor subtype is responsible for the cholinergic relaxation of the cat middle cerebral artery.

Acetylcholine↗
PubMed1987

Direct binding studies on ileal and cardiac muscarinic receptors.

1 Functional studies have indicated that muscarinic receptors in cardiac tissue differ from those in the ileum. In the present study ileal and cardiac muscarinic receptors identified by [3H]-N-methyl scopolamine ([3H]-NMS) were characterized and the selectivity of currently available ileal and atrial selective antagonists determined. 2 In terms of the current functional classification of muscarinic receptors both ileal and cardiac muscarinic receptors were of the M2 subtype based upon their low affinity for pirenzepine. 3 Cyclohexylphenyl(2-piperidinoethyl)silanol (CPPS), a highly ileal selective antagonist in functional studies, was unable to distinguish between ileal and atrial muscarinic receptors identified in binding studies. Furthermore, although AF-DX 116 and dicyclomine were able to differentiate atrial and ileal muscarinic receptors, neither compound was more than 2 fold selective. These data indicate that it is not possible to subclassify ileal and atrial muscarinic receptors using direct ligand binding studies with these antagonists. 4 In circular ileal smooth muscle, apparent heterogeneity of the M2 muscarinic receptor population was observed. Thus AF-DX 116 identified two populations of sites with affinities differing by 30 fold. These two populations of M2 muscarinic receptors may represent the typical M2 muscarinic receptors identified in cardiac tissue and the more recently discovered 'gland type' M2 muscarinic receptors. 5 The circular ileal smooth muscle tissue homogenate was able to decrease dramatically the apparent affinity of adiphenine. This activity, which appeared to result from a phenylmethylsulphonylfluoride (PMSF) sensitive protease effect, should be considered when conducting studies using this tissue preparation and compounds of similar structure to adiphenine.

Animals↗
PubMed1975

[Interactions of some parasympatholytics and structurally similar drugs with bovine serum albumin].

The interactions of the parasympatholytic drugs adiphenin, adiphenin H and propanthelin and the structurally related compounds, diphenhydramine, D-propoxyphene and methadone with bovine serum albumin (BSA) are studied by equilibrium dialysis and ultracentrifugation. The results show that BSA has a few binding sites (n less than 10) for the mentioned drugs. The association between the compounds under study and BSA are relatively weak. The binding constants are in the range of 10(3) l/Mol.

Binding Sites↗
PubMed1975

[Studies on the binding of some parasympatholytics to bovine serum albumin/measurement of relaxation times (author's transl)].

The interactions of the parasympatholytic drugs adiphenin, adiphenin H and propantheline and the structurally related compounds diphenhydramine, D-propoxyphene and methadone with bovine serum albumin (BSA) are studied by means of 1H-NMR-spectroscopy. The relaxation rates of essential protons or proton groups of the bound ligands are obtained by a plot of the observed relaxation rates, which are determined from the alterations of the line widths in the presence of BSA, versus the biopolymer concentration. From the stabilization factors R thus obtained it can be concluded that there exist defined but relatively weak associations between these drugs and BSA; both the hydrophobic aryl moieties and the ionized amino groups are involved in these interactions.

Dextropropoxyphene↗
PubMed2001

Receptor protection studies to characterize neuronal nicotinic receptors: tubocurarine prevents alkylation of adrenal nicotinic receptors.

Our laboratory has evidence that multiple nicotinic acetylcholine receptor subtypes regulate bovine adrenal catecholamine release. In the following studies, receptor protection assays were used to differentiate adrenal nicotinic receptor subpopulations. Under alkylating conditions, bromoacetylcholine (30 microM) reduced nicotinic receptor-stimulated adrenal catecholamine secretion by approximately 80%. When 100 microM tubocurarine was present during alkylation, nicotine-stimulated secretion was reduced by less than 30%. Hexamethonium (500 microM), decamethonium (500 microM), mecamylamine (50 microM), pentolinium (50 microM), adiphenine (50 microM), methyllycaconitine (1 microM) and alpha-bungarotoxin (1 microM) afforded no protection when present during alkylation. When the pharmacology of residual, tubocurarine-protected receptors was investigated, the EC50 value for nicotine's stimulatory effects on secretion significantly increased from 4.0 (2.5-6.5) microM in control cells to 9.1 (7.2-11.4) microM in tubocurarine-protected cells. In addition, the IC50 value for tubocurarine's inhibitory effects on release significantly decreased from 0.7 (0.5-0.9) microM in control cells to 0.3 (0.2-0.4) microM in tubocurarine-protected cells. These studies support the use of protection assays to characterize nicotinic receptor subpopulations.

Acetylcholine↗
PubMed1991

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. I. A microcalorimetric study.

Solution calorimetry has been employed to evaluate the stability constants and enthalpy changes associated with complex formation between alpha-, beta, or gamma-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. Data from thermal titrations of the compounds were analyzed using nonlinear least squares. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative standard enthalpy change (delta H degrees). The standard entropy change (delta S degrees) was negative, except in the case of complexes formed with gamma-CD. Of the 13 compounds studied, only 2 formed complexes with 1:2 (compound:beta-CD) stoichiometry, terfenadine . HCl and cinnarizine . 2HCl. All the others formed 1:1 complexes. The structural effect on the stability constants, thermodynamics, and inclusion geometry was explored by relating the calorimetric results to the chemical structures of the guest molecules and the cavity sizes of the CD molecules. The results suggest that one of the phenyl groups of the diphenylmethyl functionality resides in the CD cavity and is in van der Waals contact with the inside wall of the CD cavity. In the case of alpha- and beta-CDs, van der Waals interaction dominates in the stabilization. On the other hand, the interaction between these compounds and gamma-CD is largely entropically driven. Adiphenine . HCl forms a more stable complex with beta-CD than proadifen . HCl, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl group on the rim of the CD ring can influence the strength of the binding interaction.

Calorimetry↗
PubMed1974

Influence of SKF-525A congeners, strophanthidin and tissue-culture media on desensitization in frog skeletal muscle.

1 Microelectrodes have been used to follow changes in membrane potential at end-plate regions of frog skeletal muscle fibres exposed to carbachol; the depolarizing drug was applied to narrow strips of muscle in a rapidly flowing solution containing relatively impermeant anions rather than chloride.2 During prolonged applications of carbachol (10 to 20 muM), the depolarization caused by the drug showed a gradual decline which was attributed to desensitization.3 Desensitization was little if at all affected by supplementing the external solution with factors present in tissue-culture media, or by treating the muscle with strophanthidin (25 muM).4 The rate of repolarization in the presence of carbachol (10 to 20 muM) was greatly increased by the SKF-525A congeners pipenzolate bromide (10 muM) and adiphenine hydrochloride (1 muM). The desensitization-enhancing action of these compounds is discussed.

Animals↗
PubMed1987

Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes.

The affinity of a number of 'selective' agonists and antagonists has been assessed at atrial or ileal muscarinic receptors by use of in vitro functional analysis. The most selective compound for ileal muscarinic receptors was silabenzhexol (approx. 50 fold), and to a lesser extent benzhexol (approx. 5 fold). Conversely, the most selective compound for the atrial muscarinic receptors was AF-DX 116 (approx. 6 fold). The novel M1-receptor antagonist, telenzepine and other antagonists such as propantheline and isopropamide did not distinguish between atrial and ileal receptors. Dicyclomine, adiphenine, hexahydroadiphenine and oxyphenonium exhibited competitive antagonism at atrial receptors but non-competitive antagonism at ileal receptors. No conclusions could, therefore, be drawn with regard to their selectivity. The agonists, arecaidine propargyl ester (APE), ethoxyethyltriethylammonium (EOE) and carbachol, exhibited some selectivity in potency but little difference in affinity. It is concluded that the study supports the existence of ileal and atrial muscarinic receptor subtypes. However, the use of dicyclomine and related compounds in receptor classification is limited.

Animals↗
PubMed1994

Pharmacological profiles of the subtypes of muscarinic cholinoceptors that mediate aggregation of pigment in the melanophores of two species of catfish.

Using selective antagonists, including pirenzepine, adiphenine, AF-DX 116, gallamine, and 4-DAMP, we attempted to characterize the muscarinic cholinoceptors on the melanophores of the translucent glass catfish Kryptopterus bicirrhis and the mailed catfish Corydoras paleatus. The M3 receptor-selective antagonist, 4-DAMP, potently inhibited the acetylcholine-induced aggregation of pigment in both species. It appeared, therefore, that the receptors that mediated the cholinergically evoked aggregation of melanosomes in these species were of the M3 muscarinic subtype.

Acetylcholine↗
PubMed1976

Aggregation of antiacetylcholine drugs in aqueous solution: micellar properties of some diphenylmethane derivatives.

Light scattering methods have been used to examine the aggregation in aqueous solution of a series of antiacetylcholine drugs based on the diphenylmethane nucleus. The drugs investigated included adiphenine hydrochloride, piperidolate hydrochloride, benztropine mesylate, orphenadrine hydrochloride, chlorphenoxamine hydrochloride, lachesine hydrochloride, poldine methylsulphate, pipenzolate bromide, clidinium bromide, benzilonium bromide and ambutonium bromide. A micellar pattern of association was established for all compounds and critical micellar concentrations and aggregation numbers have been determined.

Acetylcholine↗
PubMed1990

Effect of noncompetitive nicotinic receptor blockers on catecholamine release from cultured adrenal chromaffin cells.

Nicotinic acetylcholine receptors are found on both muscle tissue and neuronal tissue, including adrenal chromaffin cells. Certain drugs, such as the noncompetitive ion-channel blockers and the vinca alkaloids, have been demonstrated to interact with muscle-type nicotinic receptor-associated ion channels. The objectives of these studies were: (1) to determine the effects of the noncompetitive blockers of the nicotinic receptor-associated ion-channel drugs on adrenal chromaffin cells, and (2) to establish whether the vinca alkaloids and the ion-channel drugs have similar actions on adrenal nicotinic receptors. The ion-channel drugs, adiphenine, tetracaine, quinacrine, amantadine, lidocaine and procaine, inhibited receptor-stimulated catecholamine release from cultured adrenal chromaffin cells in a concentration-dependent manner (IC50s: 2, 4, 6, 41, 55 and 87 microM, respectively). The inhibitory effects of these drugs appeared to be noncompetitive. These drugs had little or no effects on catecholamine release stimulated by depolarizing concentrations of K+ or on basal release. Our results demonstrate that the ion-channel blockers interact with adrenal nicotinic receptors in a manner similar to their interaction with muscle-type nicotinic receptors and they interfere with adrenal receptor function in a manner similar to the vinca alkaloids.

Animals↗