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R Boer

Publications and source records attributed to R Boer.

At least 55 records · Page 3Linked to original sources
PubMed1995

Modelling issues in cancer screening.

The two main goals of modelling cancer screening are data analysis and evaluation. In data analysis, analytical-numerical statistical models are used to test hypotheses about preclinical disease, the screening test, and the association between early detection and risk of dying from the cancer. Evaluation in cancer screening is supported by model-based prediction of screening effects and cost-effectiveness. Simulation models are suitable for these tasks, and can also be used to identify efficient age-ranges and intervals between screening tests. Striking differences exist between screening models for cervical cancer and breast cancer, which are the two cancer types for which screening is common practice. The two main problems in cervical cancer screening are the proportion of progressive and regressive among screen-detected lesions, and the impact of screening on incidence and mortality. In breast cancer, regression is not (yet) a big issue, and the relationship between screening and mortality reduction has been demonstrated in randomized controlled trials (at least for women older than 50 years). The weakest link in current breast cancer models is the association between earliness of detection and improvement in prognosis. The modelling outcomes and their usefulness are decisively influenced by the data sets that were used in quantifying the model, and the subclassifications of the data that were considered. New or pending modelling issues include HPV-based screening in cervical cancer, screening models for colorectal cancer, the use of surrogate outcome measures and model-based meta-analysis of screening trials.

Breast Neoplasms↗
PubMed1995

B9209-005, an azido derivative of the chemosensitizer dexniguldipine-HCl, photolabels P-glycoprotein.

P-glycoprotein is an energy-dependent drug extrusion pump for a variety of anticancer drugs and is involved in the development of multidrug resistance in cancer. Dexniguldipine-HCl is a potent chemosensitizer for P-glycoprotein-mediated multidrug resistance in vitro, and clinical phase I/II trials are underway. To investigate the mechanisms of chemosensitization and to identify the binding sites for dexniguldipine-HCl on target proteins involved in chemosensitization, [3H]B9209-005, an azido derivative of dexniguldipine-HCl, was synthesized and used as a photoaffinity ligand. In two models of multidrug resistance reversal, i.e., sensitization to vincristine and modulation of rhodamine-123 uptake, B9209-005 and dexniguldipine-HCl showed identical biological activities. Photoaffinity labeling experiments with [3H]B9209-005 in cell membranes from multidrug-resistant CCRF ADR-5000 cells, in comparison with labeling experiments with [3H]azidopine (an established photoaffinity ligand for P-glycoprotein), showed that [3H]B9209-005 labeled two proteins, with apparent molecular masses of 170 and 95 kDa. The pharmacological specificity of labeling was demonstrated by inhibition of photoincorporation by several cytostatic drugs transported by P-glycoprotein, as well as by chemosensitizers. Immunoprecipitation of the labeled proteins with the P-glycoprotein-specific monoclonal antibody C 219 and with a site-directed polyclonal antibody to the amino-terminal sequence of P-glycoprotein (amino acids 389-406) identified these proteins as intact P-glycoprotein and the amino-terminal fragment thereof. No specific labeling was obtained in the drug-sensitive parent cell line CCRF-CEM, which is devoid of significant P-glycoprotein expression. Maximal labeling of 17 pmol of the 170-kDa protein/mg of crude membrane protein was obtained. The affinity of [3H]B9209-005 for binding to and photoincorporation into P-glycoprotein was 5-fold greater than that of [3H]azidopine, and photoincorporation of [3H]B9209-005 showed a different photoincorporation pattern, compared with [3H]azidopine, in that the latter compound was incorporated specifically into the carboxyl-terminal 55-kDa fragment of P-glycoprotein. In contrast to [3H]azidopine, no specific labeling of this fragment was obtained with [3H]B9209-005, indicating different binding sites for or different photoincorporation of the two dihydropyridine ligands. Because B9209-005 carries the photoreactive azido group in the dihydropyridine moiety, whereas the azido group of azidopine is located in the side chain, these results suggest that the dihydropyridine moiety of the two compounds probably interacts with the amino-terminal part of P-glycoprotein, whereas the side chains react preferentially with the carboxyl-terminal 55-kDa fragment.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Dexniguldipine-HCl is a potent allosteric inhibitor of [3H]vinblastine binding to P-glycoprotein of CCRF ADR 5000 cells.

Cell membranes were prepared from the multidrug resistant, P-glycoprotein expressing human lymphoblastoid cell line CCRF-ADR 5000. The P-glycoprotein of these membranes possessed high affinity binding sites for [3H]vinblastine, with a Kd of 8 +/- 2 nM and Bmax of 17 +/- 8 pmol/mg of protein. The binding of [3H]vinblastine to P-glycoprotein was not ATP-dependent, and was inhibited by cytotoxic drugs with the following potency order; vincristine > doxorubicin > etoposide. The 1,4-dihydropyridine and multidrug resistance reversing agent, dexniguldipine-HCl, inhibited binding with a Ki value of 37 nM. The multidrug resistance reversing agent cyclosporin A, and the cytotoxics doxorubicin and etoposide did not alter the kinetics of [3H]vinblastine dissociation from P-glycoprotein; however, the 1,4-dihydropyridines dexniguldipine-HCl and nicardipine accelerated dissociation of [3H]vinblastine. These data suggest that P-glycoprotein possesses at least two allosterically coupled drug acceptor sites; receptor site 1 which binds vinblastine, doxorubucin, etoposide and cyclosporin A, and receptor site 2 which binds dexniguldipine-HCl and other 1,4-dihydropyridines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Prediction of the effects and costs of breast-cancer screening in Germany.

Although breast-cancer screening programmes are now being introduced it is still debated whether this is an appropriate policy for all European countries. Taking into account empirical data from 2 regional pilot screening projects, this study has evaluated the effects and costs of a nationwide breast-cancer screening programme in Germany. Special attention was paid to the decentralized German health-care system and to the influence of attendance, interval and age group. The recent results of the analysis of the Swedish randomized screening trials were used to estimate the improvement in prognosis after early detection of breast cancer. Our analysis shows that a programme providing for the screening of women aged 50-69 at 2-year intervals might be expected to result in a decrease in mortality from breast cancer estimated at 11% for the total German population, representing 2,100 deaths from breast cancer prevented each year. The cost per life-year gained was assessed at between DM 18,800 and DM 25,300 for this scenario; 2 to 3 times less favourable than in the UK and The Netherlands. The sensitivity of mammography was estimated to be 12% lower than in The Netherlands and the attendance rate was calculated at 47% on average. A greater effort to ensure the quality of the screening programme and to improve the invitation system might finally lead to much better results. The mortality reduction might be as much as 18% if the attendance and the sensitivity of the screening could be improved to the Dutch level.

Aged↗
PubMed1994

Influence of dexniguldipine-HC1 on rhodamine-123 accumulation in a multidrug-resistant leukaemia cell line: comparison with other chemosensitisers.

In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. Among other mechanisms, the expression and pumping activity of P-glycoprotein (PGP) in the membrane of resistant cancer cells is responsible for the reduced uptake of cytostatics. The blockade or inhibition of PGP activity by chemosensitisers seems to be a tenable way to restore sensitivity to antineoplastic drugs and therapeutic efficacy. In the present work the influence of the new chemosensitiser dexniguldipine on rhodamine-123 accumulation in multidrug-resistant leukaemia cells was investigated. Dexniguldipine increases cellular rhodamine-123 accumulation dose-dependently.pEC50 values (-log concentration of drug showing a half maximal effect) in accumulation studies are dependent on pH of the test system and are in the range of 6.5 (pH 7.2) to 7.2 (pH 8.0) for dexniguldipine. In comparison with other chemosensitisers such as SDZ PSC 833, cyclosporin A, verapamil, dipyridamole, quinidine and amiodarone, dexniguldipine is the most potent drug in this test system. In addition to equilibrium measurements of rhodamine-123 accumulation, efflux of rhodamine-123 was analysed in the absence and presence of chemosensitisers. A clear dose-dependency was seen and, moreover, a dramatic decrease in efflux rates was achieved in the presence of chemosensitisers. The described system can be used to investigate PGP-mediated drug transport on a pharmacological and biochemical basis.

Antineoplastic Agents↗
PubMed1993

How cost-effective is breast cancer screening in different EC countries?

Should the decision to start breast cancer screening in the Netherlands and in the U.K. be followed by other EC countries? This question has been addressed in an exploratory analysis of the differences in cost-effectiveness of breast cancer screening in Spain, France, the U.K. and the Netherlands. A detailed cost-effectiveness analysis of breast cancer screening in the Netherlands has been used as the starting point. Country specific data on incidence, mortality, demography, screening organisation and price levels in health care have been used to predict the costs and effects of nationwide screening programmes, in which women aged 50-70 are invited for 2-yearly mammographic screening. The relative effect of screening is highest in the U.K. (16.55 life-years gained per 1000 screens) and lowest in Spain (8.23 life-years gained per 1000 screens). The cost per screen is highest in Spain (38 pounds) and lowest in the U.K. (18 pounds). In comparison with the yearly health expenditures per capita, the cost per life-year gained is 2.8 times higher in the Netherlands, 3.1 times higher in the U.K., 6.5 times higher in France and 20.6 times higher in Spain. These marked differences show that no uniform policy recommendations for breast cancer screening can be made for all countries of the EC.

Aged↗
PubMed1993

Cost-effectiveness of mammographic screening in Australia.

The purpose of this research was to estimate the cost-effectiveness of mammographic screening to supplement the results of the National Evaluation of Breast Cancer Screening which identified the mortality benefit as the most sensitive parameter. This appraisal used a different computer model, MISCAN, which models the effects of introducing a national screening program into a previously unscreened population, rather than basing estimates on the assumption of a fully established program. For the 40 to 49 age group a mortality reduction of 8 per cent was assumed, rather than the 30 per cent estimate utilised in the National Evaluation. The revised estimate is based on the two Swedish trials (Malmo and WE). New estimates for treatment costs were also incorporated into the MISCAN model. The cost-effectiveness of the policy recommended in the National Evaluation Report, $11,000 per life year saved with two-yearly screening of women over 40, is estimated by the MISCAN model to be $20,300. These differences arise partly from the difference in mortality effects for the 40 to 49 age group, but also from differences inherent in the steady-state and dynamic population approaches to modelling premature deaths averted. The MISCAN results confirm that screening for women over 50 is more cost-effective than screening women under 50. Screening all women aged 50 to 69 every two to three years is reasonable value for money. For women aged 40 to 49 the mortality benefit and cost-effectiveness is less clear, and it would be prudent to allow screening in this group until further evidence is available.

Adult↗
PubMed1993

Heterogeneity of L-type calcium channel alpha 1 subunits: stereoselective discrimination of different populations by the novel 1,4-dihydropyridine B 874-67.

The basic (pKa = 8.49) 1,4-dihydropyridine B 874-67 [[3-(C1R,2S)- 2-methylamino-1-phenylpropyl]-5-methyl-1,4-dihydro-2,6-dimethyl-(4R)-4-( 3-nitrophenyl)pyridine-3,5-dicarboxylate hydrochloride] has unique properties; it can discriminate two populations of alpha 1 subunits in 1,4-dihydropyridine-sensitive calcium channels labeled with the neutral 1,4-dihydropyridine (+)-[3H]PN 200-110. The two populations, which occur in proportions of approximately 2:1 in rabbit skeletal muscle membranes and highly purified calcium channel preparations, differ approximately 20-fold in their affinity. The corresponding diastereomer, B 874-66, and other 1,4-dihydropyridines (neutral, basic, or permanently charged) do not share this property. The two populations were observed at 2 degrees, 22 degrees, and 37 degrees in similar proportions. Heterogeneity was also observed for guinea pig heart membrane calcium channels labeled with (+)-[3H]PN 200-110. Heterotropic allosteric regulators, Ca2+, and Mg2+, but not Ba2+ and Ni2+, abolished the discriminatory activity of B 874-67 at 2 degrees and 22 degrees, regardless of whether binding of the neutral 1,4-dihydropyridine was stimulated or inhibited. It is proposed that the two alpha 1 subunit populations differ with respect to their 1,4-dihydropyridine binding domain. The structural basis for the two populations is unclear but may relate to the functional heterogeneity of membrane-bound and highly purified calcium channel preparations previously observed by others.

Allosteric Regulation↗
PubMed1992

The adrenoceptor agonist, SDZ NVI 085, discriminates between alpha 1A- and alpha 1B-adrenoceptor subtypes in vas deferens, kidney and aorta of the rat.

The potency of the alpha 1-adrenoceptor agonist (-)-(4aR, 10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H -naphth [2,3-b]-1,4-oxazine (SDZ NVI 085) was investigated both in isolated vas deferens and perfused kidney of the rat, two tissues with alpha 1A-adrenoceptor subtype characteristics, and in the rat thoracic aorta, in which the contribution of different alpha 1-adrenoceptor subtypes mediating contraction is controversial. In vas deferens and kidney, SDZ NVI 085 evoked smooth muscle contraction and vascular constriction and was of similar potency to L-phenylephrine. Contractions of vas deferens in response to (-)-noradrenaline and SDZ NVI 085 were resistant to chloroethylclonidine treatment (3 x 10(-5) M), sensitive to (+/-)-isradipine (10(-8) M) and competitively antagonized by 5-methyl-urapidil (pA2 = 9.04 and 8.82, respectively). The potencies of a number of alpha 1A-/alpha 1B-adrenoceptor-discriminating antagonists to reverse renal vasoconstriction due to either (-)-noradrenaline or SDZ NVI 085, and their affinities in vas deferens correlated significantly with their pKi values at alpha 1A binding sites in rat cortex. In rat aorta, SDZ NVI 085 up to 5 x 10(-4) M failed to evoke contraction. The affinities of subtype-selective antagonists determined in aorta correlated significantly with the pKi values at alpha 1B binding sites but differed from pKi values at alpha 1A sites in rat cortex. Thus, the contractile alpha 1-adrenoceptor in rat aorta can be best characterized as B subtype. SDZ NVI 085 might be a selective alpha 1A-adrenoceptor agonist and thus be used as a new tool either to detect (rat vas deferens and kidney) or exclude (rat aorta) a contribution of alpha 1A-adrenoceptors functionally involved in smooth muscle contraction.

Adrenergic alpha-Agonists↗
PubMed1991

Vasodilatation elicited by 5-HT1A receptor agonists in constant-pressure-perfused rat kidney is mediated by blockade of alpha 1A-adrenoceptors.

The vasodilator mechanism of the putative serotonin1A (5-HT) receptor agonists, urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated in constant-pressure perfused rat kidneys. The compounds (10(-12)-10(-7) mol bolus injection) neither enhanced basal flow nor evoked vasodilatation in kidneys preconstricted by 27 mM KCl, 1.5 mM BaCl2 or 10(-6) M prostaglandin (PG)F2 alpha, but evoked a dose-dependent, reversible and spiroxatrine-resistant increase in vasodilatation of organs preconstricted by 6 x 10(-7) M noradrenaline. 5-Carboxamidotryptamine and sumatriptan did not reverse the vasoconstriction induced by all stimuli or that induced by noradrenaline in the presence of 5-HT2 plus 5-HT3 receptor blockade. No correlation for the vasorelaxant drugs was found between their -log ED50 in rat kidney and pKi values at 5-HT1A binding sites in pig cortex as determined in radioligand experiments. The relaxation in rat kidney induced by 5-HT1A receptor agonists and alpha 1A-adrenoceptor-selective antagonists (WB 4101 and (+)-niguldipine) was significantly correlated with pKi values at alpha 1A binding sites in rat cortex and the pA2 values derived from contraction studies for competitive antagonism at alpha 1-adrenoceptors in prostatic portions of the rat vas deferens, but differed from pKi values for alpha 1B binding sites in rat cortex. Thus, the vasodilator effect of the 5-HT1A receptor agonists urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-OH-DPAT in the noradrenaline-perfused rat kidney appears to be mediated by their concomitant alpha 1A-adrenoceptor blockade. No evidence for a vasodilator effect mediated through 5-HT1A receptors was found under our experimental conditions.

Adrenergic alpha-Antagonists↗
PubMed1991

Telenzepine inhibits electrically-stimulated, acetylcholine plus histamine-mediated acid secretion in the mouse isolated stomach by blockade of M1 muscarine receptors.

1. The muscarine receptor mediating electrically-stimulated acid secretion in the mouse isolated stomach was characterized using a variety of muscarine receptor antagonists confirming the M1 nature of the antagonist effect of telenzepine. 2. Field stimulation (7 V, 10 Hz, 0.5 ms) resulted in a plateau acid secretion over at least 90 min which was completely blocked by either 1 mumol/l TTX or H2 receptor antagonists (100 mumol/l cimetidine or 10 mumol/l lupitidine). Ranitidine, which is known to potently inhibit mucosal acetylcholine esterase, was ineffective. Compound 48/80 at 100 mumol/l, which depletes mucosal histamine stores, initially mimicked electrical stimulation but subsequently prevented it from inducing acid secretion. 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion. The percentages inhibition were plotted against binding affinities of the antagonists at either M1, M2 or M3 binding sites. A statistically significant correlation between functional and binding data was detected only when based on M1 affinities. 4. It is concluded that field stimulation, which probably mimicks vagal drive, results in muscarinic M1 receptor activation on paracrine cells to release histamine. Histamine then stimulates parietal cells to secrete acid. Hence, according to the present and our previous data, telenzepine inhibits acid secretion under these conditions by blocking M1 receptors at least partially located on histamine-releasing paracrine cells.

Acetylcholine↗
PubMed1990

[Efficacy of mass screening for breast cancer; reduced mortality nationally and internationally].

Breast cancer screening trials in several countries have proved to reduce breast cancer mortality. However, the trials show considerable differences in the extent of this reduction. The Swedish projects in Kopparberg/Ostergötland and Malmö are the most similar to the Dutch situation. The confidence intervals of the effect estimates of both projects are large. A critical review of all differences cannot yet lead to a conclusion on the difference in the estimated effects of both trials. Assuming equal mammographic quality in both projects, a reduction of 33% in breast cancer mortality for women in the age-group of 50 to 70 years seems a good estimate for similar projects. This assumption applied to a Dutch nationwide project, it will eventually lead to a reduction in breast cancer mortality of 16% for the entire population. In the year 2015 about 700 women will not die of breast cancer who would have without screening.

Adult↗
PubMed1990

Monoclonal antibodies against different epitopes of peptide hormones. Use of photoreactive analogues in studies on vasopressin.

In order to produce monoclonal antibodies directed against different epitopes of the neurohypophyseal hormone vasopressin, the hormone was coupled to carrier proteins via photoreactive groups at different positions in the vasopressin sequence: [2-(4-azidophenylalanine), 8-arginine]vasopressin (peptide P1, photoreactive group at position 2) and desamino-[8-N6-(4-azidophenylamidino)lysine]vasopressin (peptide P2, photoreactive group at position 8) were conjugated to thyroglobulin by flash photolysis. Monoclonal antibodies against these conjugates bound ([3H]8-arginine]vasopressin with dissociation constants ranging over 40-400 nM. Epitope analysis by means of competitive ELISA showed that the monoclonal antibody obtained with peptide P1 as hapten was directed against the C-terminal acyclic tripeptide when its conformation was stabilized by interaction with the disulphide-linked cyclic hexapeptide. In contrast, the epitope analysis of three monoclonal anti-(peptide P2) antibodies demonstrated that they recognized antigenic determinants in the cyclic hexapeptide ring, mainly the hydrophobic surface formed by Tyr2 and Phe3. Our results suggest that monoclonal antibodies against different epitopes in small peptide hormones can be generated selectively by using photoreactive peptides in such a way that different antigenic sites are exposed in the hapten-carrier conjugate.

Amino Acid Sequence↗
PubMed1990

Stereoselective inhibition of thromboxane-induced coronary vasoconstriction by 1,4-dihydropyridine calcium channel antagonists.

The biological activity of the (+)-S- and (-)-R-enantiomers of niguldipine, of the (-)-S- and (+)-R-enantiomers of felodipine and nitrendipine, and of rac-nisoldipine and rac-nimodipine was investigated in vitro and in vivo. Inhibition of coronary vasoconstriction due to the thromboxane A2 (TxA2)-mimetic U-46619 in guinea pig Langendorff hearts, displacement of (+)-[3H]isradipine from calcium channel binding sites of guinea pig skeletal muscle T-tubule membranes, and blood pressure reduction in spontaneously hypertensive rats were determined. The enantiomers were obtained by stereoselective synthesis. Cross-contamination was less than 0.5% for both S- and R-enantiomers of niguldipine and nitrendipine and less than 1% for those of felodipine. From the doses necessary for a 50% inhibition of coronary vasoconstriction, stereoselectivity ratios for (+)-(S)-/(-)-(R)-niguldipine, (-)-(S)-/(+)-(R)-felodipine, and (-)-(S)-/(+)-(R)-nitrendipine of 28, 13, and 7, respectively, were calculated. The potency ratio rac-nisoldipine/rac-nimodipine was 3.5. Ratios obtained from binding experiments and antihypertensive activity were (+)-(S)-/(-)-(R)-niguldipine = 45 and 35, (-)-(S)-/(+)-(R)-felodipine = 12 and 13, (-)-(S)-/(+)-(R)-nitrendipine = 8 and 8, and rac-nisoldipine/rac-nimodipine = 8 and 7, respectively. Highly significant correlations were found between the in vitro potency of the substances to prevent U-46619-induced coronary vasoconstriction and their affinity for calcium channel binding sites as well as their antihypertensive activity.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Pharmacological characterization of muscarine receptors of PC12 (rat phaeochromocytoma) cells.

The muscarine receptors of PC12 (rat phaeochromocytoma) cells were studied in functional and binding experiments. The catecholamine stores of PC12 cells were labelled by incubation of the cells with tritiated noradrenaline. Muscarinic agonists elicited concentration-dependent release of tritium which consisted overwhelmingly of unchanged 3H-noradrenaline. The rank order of potency was: oxotremorine greater than acetylcholine greater than muscarine = methacholine greater than carbachol greater than bethanechol. The release evoked by carbachol (0.1 mmol/l) was inhibited with high potency by the M1-selective antagonist telenzepine (pKi = 8.82), with intermediate potency by pirenzepine (pKi = 7.00) and with low potency by the M2-selective antagonist AF-DX 116 (pKi = 5.74). The binding of 3H-N-methylscopolamine to PC12 membranes was inhibited by various non-selective and subtype-selective muscarinic antagonists with the following rank order of potency: telenzepine = atropine greater than 4-DAMP greater than dicyclomine greater than pirenzepine greater than HHSiD much greater than AF-DX 116. A similar rank order was obtained for the inhibition by these compounds of 3H-telenzepine binding to M1-receptors in membranes of the cerebral cortex of the guinea pig. The Hill coefficients for inhibition of 3H-N-methylscopolamine binding (to PC12 membranes) by pirenzepine, telenzepine and AF-DX 116 were below unity. Specific binding of both 3H-telenzepine and 3H-N-methylscopolamine to muscarine receptors of PC12 membranes was saturable and of high affinity; the maximal number of binding sites was higher for 3H-N-methylscopolamine than for 3H-telenzepine (calculated for the active (+)enantiomer). PC12 cells are presumably endowed with more than one subtype of muscarine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1990

Characterization of the muscarine receptor type on paracrine cells activated by McN-A-343 in the mouse isolated stomach.

An attempt was made to characterize the muscarine receptor type(s) involved in acid secretion in the mouse isolated stomach when stimulated by the muscarinic agonist McN-A-343. A series of 8 muscarinic antagonists was used with preference for M1 receptors (telenzepine and pirenzepine), M1 and M2 receptors (secoverine), M2 receptors (AF-DX 116 and himbacine) and M1 and M3 receptors (p-F-HHSiD and HHSiD). BTM-1086 was used as a high affinity antagonist at the M1 receptor however with little selectivity. Receptor type preferences were determined in binding experiments with [3H]telenzepine in cortical membranes (M1) and [3H]N-methylscopolamine in atrial (M2) or salivary gland (M3) membranes, derived from guinea pigs. No antagonist with M3 preference could be identified in the binding studies. A fixed antagonist concentration of 1 mumol/l was used to antagonize acid secretion stimulated by 10 mumol/l McN-A-343. By plotting the percentage inhibition obtained in the functional test against the Ki values determined in binding experiments for each antagonist at M1, M2 and M3 binding sites, an affinity-inhibition curve could only be constructed when based on the antagonist affinities to the M1 receptor. No statistically significant fit was found using antagonist affinities to the M2 or M3 receptor. Thus, in accordance with the presumed M1 selectivity of the agonist McN-A-343, the rank order of potencies of different antagonists point to the M1 nature of the muscarine receptor which stimulates acid secretion in the mouse isolated stomach upon activation by McN-A-343.(ABSTRACT TRUNCATED AT 250 WORDS)

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