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PubMed1985

Failure of gallamine and pancuronium to inhibit selectively (-)-[3H]quinuclidinyl benzilate binding in guinea-pig atria.

Binding of (-)-[3H]quinuclidinyl benzilate (QNB) to muscarinic sites in guinea-pig atrial and ileal longitudinal muscle homogenates showed the presence of a single population of binding sites in atria (KD = 41 (32-53) (95% confidence limits) pM; Bmax = 0.225 +/- 0.02 pmol/mg protein (3)) and two binding sites in the ileum (KD = 20.9 (8.8-49) pM and 11.3 nM; Bmax = 0.436 +/- 0.09 and 11.85 +/- 2.63 pmol/mg protein (4), respectively). Atropine, gallamine, and pancuronium displaced (-)-[3H]QNB binding from the high affinity binding sites in the two tissues in a dose-dependent manner with -log Ki values of 8.6, 6.4, and 6.9, respectively, in atria and 8.7, 6.8, and 6.9, respectively, in ileal longitudinal muscle. The lack of selectivity of gallamine and pancuronium in binding experiments differed from results obtained in isolated tissue experiments where these antagonists showed a marked difference in their ability to antagonize cholinomimetics in the two tissues. In addition, the Ki values for gallamine and pancuronium in ileal homogenates were ca. 130- and 16-fold lower, respectively, than their KB values determined from isolated tissue experiments. Attempts to correlate data from binding experiments and isolated tissue experiments using combinations of antagonists led to variable results attributed to differences in the rates of dissociation of the antagonists from muscarinic receptors. It is concluded that the interaction of gallamine or pancuronium with agonists or antagonists at muscarinic receptors is not a simple bimolecular interaction.

Animals↗
PubMed1990

Cerebrovascular transport of [125I]quinuclidinyl benzilate, [3H]cyclofoxy, and [14C]iodoantipyrine.

The transport rate constants across rat brain capillaries of a muscarinic acetylcholine receptor antagonist, [125I]quinuclidinyl benzilate (IQNB), an opiate receptor antagonist, [3H]cyclofoxy (CF), and a highly diffusible blood flow indicator, [14C]iodoantipyrine (IAP), were determined by the indicator-diffusion technique and a model that includes a distribution of capillary transit times and a homogeneous distribution of the test compound in the tissue parenchyma. The mean influx extraction ratio (E1) of IAP was greater than 0.91, and E1 for CF and IQNB was 0.56-0.79 and 0.34-0.46, respectively. The order of lipid solubility was IQNB greater than IAP greater than CF; the apparent discrepancy (high lipid solubility and low permeability) of IQNB was partly due to intravascular binding to plasma protein and red blood cells. The observed initial tissue distribution volumes (lambda 1, ml/g brain) for IQNB (0.09-0.17), CF (0.51), and IAP (0.71) were compared with those estimated for the unbound free ligand in blood (lambda a, ml/g brain; IQNB = 1.3-2.3, CF = 0.88, and IAP = 1.4). These findings suggest that the binding of lipid-soluble radioligands and drugs to plasma proteins and red blood cells can be a major determinant of transport across the blood-brain barrier and the apparent distribution volume of the ligand in brain tissue.

Animals↗
PubMed1983

Autoradiographic localization of quinuclidinyl benzilate binding to rat pituitary gland.

The location of muscarinic receptors in the rat pituitary gland was examined with an autoradiographic technique. Slides containing 10 or 20 micron horizontal sections of tissue were incubated in a solution of 1 n M[3H]quinuclidinyl benzilate (QNB) in phosphate-buffered saline to label muscarinic receptors. Autoradiograms were produced by placing the slides into X-ray cassettes with tritium-sensitive film and processing the film 8-10 weeks later. Minimal binding occurred when sections were incubated in 1 nM[3H]QNB plus 1 microM atropine. Highest specific binding of QNB was found in the anterior and intermediate lobes along their border with the pituitary cleft. Patches of high binding were also seen penetrating the intermediate lobe and at the border between the intermediate and neural lobes. The remainder of the intermediate lobe had background density of autoradiographic grains. Moderate density of specific binding was found throughout the anterior lobe. Low specific binding occurred in the neural lobe.

Animals↗
PubMed1979

Muscarinic receptors of the pancreas: a correlation between displacement of (3 H)-quinuclidinyl benzilate binding and amylase secretion.

(3H)-quinuclidinyl benzilate [(3H)-QNB], A potent muscarinic antagonist, was used as a tool to reveal the presence of muscarinic receptors in rat pancreas. Binding assays were performed on a 49,000 g pellet. Known muscarinic antagonists and agonists were used for competition assays on (3N)-QNB binding and studies on amylase secretion in vitro. A correlation was established between the binding assays and the studies on amylase release which suggests that the binding sites and those involved in the cholinergic control of pancreatic enzyme secretion are similar.

Acetylcholine↗
PubMed1991

Effect of the steroidal alkaloid buxaminol-E on blood pressure, acetylcholinesterase activity and (3H)quinuclidinyl benzilate binding in cerebral cortex.

Pharmacological properties of the steroidal alkaloid buxaminol-E isolated from Buxus sempervirens varietas bullata were studied in relation to the cholinergic nervous system. In anaesthetised cats buxaminol-E (1.25 mumol/kg) initially induced a small short-lasting increase in blood pressure followed by marked hypotension. Atropine (1.47 mumol/kg) inhibited the hypotensive effect almost completely and methylatropine (1.47 mumol/kg) partially. Buxaminol-E and the muscarinic agonists McN-A-343 and bethanechol inhibited the binding of the muscarinic antagonist (3H)quinuclidinyl benzilate in cat and rabbit cerebral cortex membranes in decreasing order of potency. In about 10-fold higher concentrations they also inhibited acetylcholinesterase activity in cat cerebral cortex in the same order of potency. The results suggest that the hypotensive effect of buxaminol-E could be due to both central and peripheral activation of muscarinic receptors, and to a lesser degree to inhibition of acetylcholinesterase activity.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1986

Effects of deoxyribonuclease I and neuraminidase treatments on the specific binding of 3H-prazosin and 3H-quinuclidinyl benzilate (3H-QNB) to alpha-adrenergic and muscarinic receptors in rat myocardial membranes.

The effects of neuraminidase and deoxyribonuclease I (DNase) treatments on the specific binding of 3H-prazosin and 3H-quinuclidinyl benzilate (3H-QNB) to alpha-adrenoceptors and muscarinic cholinergic receptors in the membrane of the rat myocardium was examined, and the dissociation constant (Kd) and the maximum number of binding sites (Bmax) was analyzed using the method of Scatchard analysis. Although no changes in Kd values were observed when DNA or sialic acid was removed from cardiac muscles by treatments with DNase or neuraminidase, the Bmax values of alpha-adrenergic and muscarinic receptors were markedly decreased after treatment with DNase, while neuraminidase treatment induced an increase in the Bmax values of the alpha-adrenoceptors. The possibility that these results provide the basis for elucidation of the characteristics of these receptors in the rat myocardium was discussed.

Animals↗
PubMed1998

Age-related effects of rolipram on [3H]quinuclidinyl benzilate and [3H]phorbol 12,13-dibutyrate binding in the rat brain.

Cholinergic neurotransmission and protein kinase C (PKC) in the brain play important roles in the processes of cognitive function. In this study, we examined the effect of chronic treatment with rolipram, a 3',5'-cyclic adenosine monophosphate (cyclic AMP)-selective phosphodiesterase inhibitor, on age-related changes in [3H]quinuclidinyl benzilate (QNB) and [3H]phorbol 12,13-dibutyrate (PDBu) binding, which labeled brain muscarinic cholinergic receptors and PKC, respectively. Rolipram was administered per os to young (15 weeks old) and old (80 weeks old) Wistar rats at dosage of 0.01 mg/kg and 0.1 mg/kg once a day over 4 weeks. Then, quantitative in vitro autoradiography was performed. Control old rats showed elevations in [3H]PDBu binding in the hippocampus and the cerebellum compared to young rats, but [3H]QNB binding was largely unchanged. Chronic treatment of the old rats with the higher dose of rolipram led to reductions in [3H]QNB and [3H]PDBu binding in many brain regions. However, the same treatment of the young rats induced no or minimal effect. Thus, the response of the brain to rolipram was different between young and old rats. These results suggest that the cyclic AMP-selective phosphodiesterase system in the brain is modified during aging, modulating subsequently cholinergic neurotransmission and PKC activity exclusively in old rat brains.

Aging↗
PubMed1976

[Studies on the absorption of benzilic acid esters of homologous dimethyl-(2-hydroxyethyl)-alkylammonium bromides through buccal mucosa. 5th communication: On optimum bioavailability of homologous quaternary ammonium compounds (author's transl)].

Distribution studies in vitro predict increasing absorption rates in vivo with increasing distribution coefficients up to a limiting value. Buccal absorption tests with homologous, quaternary cholinesterbromides of benzilic acid do not confirm this hypothesis. The reasons could be the rather hydrophilic properties of the mucosal membranes and thus adsorption of drug to the mucosa. The evaluation of results with undissociated homologous carboxylic acids, however, shows a good correlation between the prediction from in vitro studies and the buccal absorption test.

Absorption↗
PubMed1975

[The optimization of the availability of homologous quaternary ammonium compounds. 2. In vitro studies on the partition of homologous benzilic acid esters of dimethyl-(2-hydroxyethyl)-alkylammonium bromides].

The partition of homologous quaternary esters of benzilic acid is studied in a modified three-phase model according to Schulmann (water-n-octanol-water). The logarithms of the partition coefficients of the compounds increase linearly with increasing alkyl chain. The rate determining step for the interphase transport of hydrophilic compound is the diffusion through the organic diffusion layer. The rate constants for the transfer from the aqueous to the organic phase increase linearly with the corresponding partition coefficient, whereas the rate constants for the reverse reaction are not influenced. With increasing chain length the diffusion through the aqueous diffusion layer becomes rate determining for the interphase transport. Thus the rate constants for the transfer from the aqueous to the organic phase are independent of partition coefficients. The rate constants for the reverse transfer are inversely proportional to the corresponding partition coefficients. The half-lives of the transfer of the homologous compounds under sink conditions show a minimum between the heptyl and octyl derivative. The equilibration time decreases with increasing agitation, concentration and temperature. The significance of the results for biological problems is discussed.

Benzilates↗
PubMed1975

[Optimating the availability of homologous quaternary ammonium compounds/3rd communication: The influence of salts on in vitro distribution of benzilic acid esters of homologous dimethyl-(2-hydroxyethyl)-alkyl-ammoniumbromides (author's transl)].

The addition of NaBr, Na-butansulfonate or Na-trichloracetat increases the partition coefficients of homologous quaternary cholinesters of benzilic acid between n-octanol and water. In a three-phase model (water/n-octanol/water) thus the rates of equilibration increase considerably for hydrophilic compounds.

Benzilates↗
PubMed1976

Mass spectrometry as an aid in the detection and identification of piperidyl benzilates and related glycolates.

On the basis of the data presented above the following conclusions may be drawn. 1. The molecular ion peaks of most of the compounds examined are relatively weak but usually easily discernible to permit molecular weight determination. 2. The mass spectra of benzilate esters exhibit a relatively intense peak at m/e 183, and monitoring of this ion can serve as a means for preliminary screening for the presence of this type of a system. 3. Related esters exhibit a similar type of fragmentation resulting in a fragment ion analogous to m/e 183 but shifted by the appropriate number of mass units according to the substituents present. 4. Cleavage of the piperidine ring-ester oxygen bond in 3 and 4-substituted isomers is followed by selective losses of hydrogen radicals to produce ions of type e, f, and g as indicated above. It is significant that in a related piperidine ring system (methylphenidate) substituted in the 2 position, the same type of cleavage results in no further hydrogen losses [16] because of charge stabilization from the ring nitrogen (ion j, Fig. 17) [17]. In other words, the tendency to form a conjugated ion following initial bond cleavage can serve as a means for identifying the position of substitution on the ring and for distinguishing positional isomers.

Benzilates↗
PubMed1991

[Analysis of muscarinic receptors on rat pancreatic acini by using 125I-quinuclidinyl benzilate and N-[3H]-methylscopolamine].

To analyze muscarinic receptors on rat pancreatic acini, we studied the binding of 125I-quinuclidinyl benzilate (125I-QNB) and N-[3H]-methylscopolamine ([3H]-NMS) to these acini. Binding of 125I-QNB and [3H]-NMS to acini was specific and reversible. 125I-QNB bound to low affinity site, which was not recognised by [3H]-NMS. However, nonspecific binding of 125I-QNB to acini was very high (46%), so 125I-QNB may be inadequate to analyze muscarinic receptor on pancreatic acini. Muscarinic receptors are classified in two groups, M1 and M2, according to affinity of pirenzepine which binds to M1 receptor selectively. Pirenzepine was 530 times less potent than atropine in inhibiting the binding of 125I-QNB, and 250 times less potent than atropine in inhibiting the binding of [3H]-NMS. These results suggest that muscarinic receptors on pancreatic acini are mainly M2 receptors.

Animals↗
PubMed1987

[Solubilization by various detergents, of the muscarinic cholinoreceptor and its complex with quinuclidinyl benzilate].

The possibilities to solubilize the rat brain cortex muscarinic acetylcholine receptor and its complex with [3H]-L-quinuclidinyl benzilate (QNB) were studied, using 14 detergents. It was shown that the native muscarinic cholinoreceptor was solubilized in addition to digitonin, also by CHAPS, with a 6% yield. Besides, the receptor-QNB complex was solubilized with the detergents Triton X-100, -102, -114, -165 (with 30% and 50% yields) and within a narrow concentration range with sodium dodecyl sulfate (50% yield). Some detergents of the Tween series, e.g., Triton X-45 and -305, as well as sodium deoxycholate and sodium oxycholate, did not solubilize the native receptor and its complex with QNB. It was found that yield of receptor solubilization did not exceed half of the total number of the receptor sites in the membranes, despite the fact that different concentrations of detergents were applied. The solubilization yield did not increase, when different mixtures of detergents were used. It was assumed that incomplete solubilization of the receptor protein reflects its heterogeneity in the membrane structure.

Animals↗
PubMed1987

Characterization of high affinity [3H]pirenzepine and (-)-[3H] quinuclidinyl benzilate binding to muscarinic cholinergic receptors in rabbit peripheral lung.

We have characterized the binding of the selective muscarinic antagonist [3H]pirenzepine ([3H])PZ) and the classical muscarinic antagonist (-)-[3H]quinuclidinyl benzilate ((-)-[3H]QNB) to muscarinic cholinergic sites in rabbit peripheral lung membranes. For both radioligands, high affinity binding with pharmacologic specificity was demonstrated. The high affinity Kd for [3H]PZ binding determined from saturation isotherms was 4.5 nM and the Kd for (-)-[3H]QNB binding was 6.2 pM. Comparison of the total binding capacity values determined by saturation experiments with [3H] PZ and (-)-[3H]QNB demonstrates that approximately 78% of the total muscarinic binding sites in rabbit peripheral lung bind [3H]PZ with high affinity. There was no significant effect of the guanine nucleotide, guanyl-5'-yl imidodiphosphate, on the inhibition of (-)-[3H]QNB binding by the muscarinic agonist carbachol in peripheral lung membranes. If the pulmonary muscarinic receptor with high affinity for PZ proves to have an important role in bronchoconstriction, its characterization could result in the development of more selective bronchodilators.

Animals↗
PubMed1985

Stereoselective L-[3H]quinuclidinyl benzilate-binding sites in nervous tissue of Aplysia californica: evidence for muscarinic receptors.

The muscarinic antagonist L-[3H]quinuclidinyl benzilate (L-[3H]QNB) binds with a high affinity (Kd = 0.77 nM) to a single population of specific sites (Bmax = 47 fmol/mg of protein) in nervous tissue of the gastropod mollusc, Aplysia. The specific L-[3H]QNB binding is displaced stereoselectively by the enantiomers of benzetimide, dexetimide, and levetimide. The pharmacologically active enantiomer, dexetimide, is more potent than levetimide as an inhibitor of L-[3H]QNB binding. Moreover, the muscarinic cholinergic ligands, scopolamine, atropine, oxotremorine, and pilocarpine are effective inhibitors of the specific L-[3H]QNB binding, whereas nicotinic receptor antagonists, decamethonium and d-tubocurarine, are considerably less effective. These pharmacological characteristics of the L-[3H]QNB-binding site provide evidence for classical muscarinic receptors in Aplysia nervous tissue. The physiological relevance of the dexetimide-displaceable L-[3H]QNB-binding site was supported by the demonstration of the sensitivity of the specific binding to thermal denaturation. Specific binding of L-[3H]QNB was also detected in nervous tissue of another marine gastropod, Pleurobranchaea californica. The characteristics of the Aplysia L-[3H]QNB-binding site are in accordance with studies of numerous vertebrate and invertebrate tissues indicating that the muscarinic cholinergic receptor site has been highly conserved through evolution.

Animals↗
PubMed1982

Muscarinic cholinergic receptor binding: in vivo depiction using single photon emission computed tomography and radioiodinated quinuclidinyl benzilate.

An attempt was made to characterize, in vivo, specific binding to the muscarinic cholinergic receptor in the calf using the radioiodinated ligand quinuclidinyl benzilate (123I-OH-QNB) and single photon detection emission computed tomography (SPECT). The supratentorial brain activity was significantly increased after the intravenous infusion of 123I-OH-QNB as compared to free 123I. Scopolamine, a muscarinic cholinergic receptor antagonist, decreased the measured brain activity when infused prior to 123I-OH-QNB consistent with pharmacologic blockade of specific receptor binding. Quantitative in vitro tissue distribution studies obtained following SPECT imaging were consistent with regionally distinct specific receptor binding in the striatum and cortical gray matter, nonspecific binding in the cerebellum, and pharmacologic blockade of specific binding sites with scopolamine. Although 123I-OH-QNB is not the ideal radioligand, our limited success will hopefully encourage the development of improved binding probes for SPECT imaging and quantitation.

Animals↗
PubMed1982

Kindled seizures selectively reduce a subpopulation of [3H]quinuclidinyl benzilate binding sites in rat dentate gyrus.

Amygdala-kindled seizures reduced significantly the total number of [3H]quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis.

Animals↗
PubMed1982

Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate.

The binding of [3H]nicotine to mouse brain has been measured and subsequently compared with the binding of [125I]alpha-bungarotoxin (alpha-BTX) and L-[3H]quinuclidinyl benzilate (QNB). The binding of nicotine was saturable, reversible, and stereospecific. The average KD and Bmax were 59 nM and 88 fmoles/mg of protein, respectively. Although the rates of association and dissociation of nicotine were temperature-dependent, the incubation temperature had no effect on either KD or Bmax. When measured at 20 degrees or 37 degrees, nicotine appeared to bind to a single class of binding sites, but a second, very low-affinity, binding site was observed at 4 degrees. Nicotine binding was unaffected by the addition of NaCl, KCl, CaCl2, or MgSO4 to the incubation medium. Nicotinic cholinergic agonists were potent inhibitors of nicotine binding; however, nicotinic antagonists were poor inhibitors. The regional distribution of binding was not uniform: midbrain and striatum contained the highest number of receptors, whereas cerebellum had the fewest. Differences in site densities, regional distribution, inhibitor potencies, and thermal denaturation indicated that nicotine binding was not the same as either QNB or alpha-BTX binding, and therefore that receptors for nicotine may represent a unique population of cholinergic receptors.

Animals↗