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Biomedical subjects

G Lambrecht

Publications and source records attributed to G Lambrecht.

At least 91 records · Page 5Linked to original sources
PubMed1989

Synthesis and muscarinic activity of a series of tertiary and quaternary N-substituted guvacine esters structurally related to arecoline and arecaidine propargyl ester.

A series of tertiary and quaternary N-substituted guvacine (1,2,5,6-tetrahydro-3-carboxy-pyridine) methyl and propargyl esters have been synthesized and tested for muscarinic/antimuscarinic activity on rat ileum and electrically paced left atria. Arecoline and arecaidine propargyl ester (APE) as well as their corresponding N-demethyl derivatives, guvacoline (norarecoline) and guvacine propargyl ester, acted as full agonists at both atrial and ileal muscarinic receptors (range of pD2-values 6.09-8.07). However, in both preparations arecoline and APE were clearly more potent (up to 15-fold) than their N-demethyl analogues. Replacement of the N-methyl group in arecoline and APE by larger substituents (ethyl, n-propyl, n-butyl, benzyl, phenylethyl) as well as N-methylation resulted in a decrease or even a complete loss of agonistic activity. In both organs, the propargyl esters usually showed higher potency than the corresponding methyl ester analogues. N-Ethylguvacine propargyl ester and APE methiodide displayed pronounced agonistic activity in the atria (pD2 approximately 6.5; intrinsic activity = 0.79 and 0.67, respectively) but behaved as competitive antagonists in the ileum (pA2 = 6.06 and 5.62, respectively). Beside the lower sensitivity to muscarinic agonists of the rat ileum as compared to rat atria, the cardioselective stimulant action of both agents may also be due to their ability to recognize structural differences between atrial M2 alpha and ileal M2 beta muscarinic receptor subtypes.

Animals↗
PubMed1989

Stereoselectivity at muscarinic receptor subtypes: observations with the enantiomers of phenglutarimide.

The affinity of the enantiomers of phenglutarimide at three muscarinic receptor subtypes was examined in vitro using field-stimulated rabbit vas deferens (M1 receptors) and guinea pig atria (M2 alpha receptors) and ileum (M2 beta receptors). Extremely high stereoselectivity was observed and higher affinities (up to 6000-fold) were found for the (+)-S-enantiomer. The stereoselectivity ratios were different at the three subtypes, and the stereochemical demands made by the muscarinic receptors were most stringent at M1 receptors. (+)-(S)-Phenglutarimide was found to be a potent M1-selective antagonist (pA2 at M1 = 8.53). Its receptor selectivity profile is qualitatively similar to that of pirenzepine. (-)-(R)-Phenglutarimide showed no comparable discriminatory properties.

Animals↗
PubMed1989

Different muscarine receptors mediate the prejunctional inhibition of [3H]-noradrenaline release in rat or guinea-pig iris and the contraction of the rabbit iris sphincter muscle.

To investigate the muscarine receptor type mediating inhibition of [3H]-noradrenaline release from the isolated rat and guinea-pig iris we have determined the potency of antimuscarinic drugs to antagonize the methacholine-induced inhibition of [3H]-noradrenaline overflow evoked by field stimulation (3 Hz, 2 min). The prejunctional apparent affinities were compared with those obtained for postjunctional muscarine receptors mediating the methacholine-induced contraction of the isolated rabbit iris sphincter muscle. Prejunctional apparent affinity constants of pirenzepine (6.67), himbacine (8.51), methoctramine (7.92), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 8.00), hexahydro-difenidol enantiomers (6.92, (R); 5.77, (S)) in the rat iris and methoctramine (7.58) in the guinea-pig iris indicate the presence of M2 receptors. Although the postjunctional affinity constants in the rabbit iris sphincter of methoctramine (5.93), gallamine (3.92), and 4-DAMP (9.07) confirm our previous suggestions of the presence of M3-like receptors, the results obtained with the hexahydro-difenidol enantiomers do not agree with that concept. The postjunctional affinity constants of the hexahydro-difenidol enantiomers were not different from the prejunctional values (6.86, (R); 5.55, (S)), indicating a similar and low degree of stereoselectivity for these stereoisomers at both receptor sites (14 and 17, (R)/(S)-ratios, respectively). Hence, the postjunctional muscarine receptor in the rabbit iris sphincter fails to exhibit the high degree of stereoselectivity observed for hexahydro-difenidol enantiomers at M3 receptors on other smooth muscles.

Animals↗
PubMed1989

Effect of M2 muscarinic receptor antagonist 4-DAMP, on prostaglandin synthesis and mechanical function in the isolated rabbit heart.

1. Muscarinic agonist acetylcholine (ACh) (non-selective) and arecaidine propargyl ester (APE) (M2 selective agonist) produced a increase in the output of 6-keto PGF1 alpha and a decrease in the heart rate and myocardial developed tension in a dose-dependent manner. 2. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect--an initial vasodilation followed by vasoconstriction. 3. The increase in 6-keto PGF1 alpha output elicited by 3 nmol of ACh or APE was inhibited by 10 nM of classical muscarinic receptor antagonist atropine or by the selective M2 beta muscarinic receptor antagonist 4-(diphenylacetoxy-N-methyl piperidine) methiodide (4-DAMP). 4. The decrease in heart rate and myocardial developed tension produced by ACh and APE was attenuated by atropine and 4-DAMP. The coronary vasodilator effect of ACh and APE and the vasoconstrictor effect of APE were also attenuated by both of these muscarinic antagonists.

Animals↗
PubMed1989

Structure-activity relationships of new analogues of arecaidine propargyl ester at muscarinic M1 and M2 receptor subtypes.

1. The potency of arecaidine propargyl ester (APE) and of several analogues containing a modified ester side chain has been assessed at M1 and M2 muscarinic receptor subtypes. APE was shown to act as a potent agonist at ganglionic M1 receptors in the pithed rat, at M2 receptors in guinea-pig isolated atria (-log EC50 = 8.22) and ileum (-log EC50 = 7.77). 2. The arecaidine 2-butynyl and 2-pentynyl esters were approximately equipotent with APE at M1 and M2 receptors, whereas the 2-hexynyl derivative was found to be less potent than APE in atria (-log EC50 = 6.80) and ileum (-log EC50 = 6.70) by about one order of magnitude. The 2-heptynyl and 3-phenyl propargyl esters exhibited no agonist actions in atria and ileum. 3. Shifting the triple bond from the 2 to the 3 position and introducing a bulky group at position 1 of the ester side chain of APE and analogues resulted in competitive antagonists (pA2 ranging from 4.9 to 7.3). 4. APE and its 2-butynyl analogue showed some agonistic selectivity for cardiac M2 receptors (potency ratio, ileum/atria = 2.8 and 4.6 respectively). All antagonists in this series of compounds were not selective in terms of affinity since their pA2 values at cardiac and ileal M2 receptors were similar (potency ratios, ileum/atria = 0.4 to 1.2).

Animals↗
PubMed1989

Antagonism of platelet activating factor-induced chemiluminescence in guinea-pig peritoneal macrophages in differing states of activation.

1. The effects of the platelet activating factor (Paf) antagonists alprazolam, BN 52021, kadsurenone, L 652,731 and SRI 63119 have been studied on Paf-induced chemiluminescence (CL) of guinea-pig, C. parvum-activated peritoneal macrophages in vitro. 2. All antagonists produced a shift to the right in the dose-response curve to Paf (0.001-10 mumol l-1). Schild plots for BN 52021, L 652,731, kadsurenone and SRI 63119 were linear, but only for BN 52021 and kadsurenone did the mean slope not differ significantly from unity. Mean pA2 values for BN 52021 and kadsurenone were 6.60 +/- 0.05 and 6.41 +/- 0.14 (mean + s.e.mean) respectively. Calculation of IC50 values for all antagonists (at 0.1 mumol l-1 Paf) gave an order of potency: L 652731 greater than kadsurenone greater than or equal to BN 52021 greater than alprazolam greater than SRI 63119. 3. When individual pA2 values for BN 52021 and kadsurenone were plotted against the maximal CL response to Paf of cell suspensions in the absence of antagonist (reflecting the degree of activation of the macrophages by the C. parvum), it was found that the affinity of both antagonists for macrophage Paf receptors remained relatively constant irrespective of the activation state of the cells. 4. We conclude that activation of guinea-pig peritoneal macrophages does not account for the increased affinity for macrophage Paf receptors previously observed for kadsurenone. Kadsurenone and BN 52021 presumably bind to a site on Paf receptors which is not affected by the activation process, while alprazolam and SRI 63119 are non-specific antagonists. The reason for the difference between the competitive nature of kadsurenone and its structural analogue L 652,731 is unclear.

Alprazolam↗
PubMed1989

Binding and functional properties of antimuscarinics of the hexocyclium/sila-hexocyclium and hexahydro-diphenidol/hexahydro-sila-diphenidol type to muscarinic receptor subtypes.

1. In an attempt to assess the structural requirements for the muscarinic receptor selectivity of hexahydro-diphenidol (hexahydro-difenidol) and hexahydro-sila-diphenidol (hexahydro-sila-difenidol), a series of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB-OK 1 cells as well as in rat heart and pancreas. 2. The action of these antagonists at muscarinic receptors mediating negative inotropic responses in guinea-pig atria and ileal contractions has also been assessed. 3. Antagonist binding data indicated that NB-OK 1 cells (M1 type) as well as rat heart (cardiac type) and pancreas (glandular/smooth muscle type) possess different muscarinic receptor subtypes. 4. A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea-pig atria and ileum. This implies that the muscarinic binding sites in rat heart and the receptors in guinea-pig atria are essentially similar, but different from those in pancreas and ileum. 5. The antimuscarinic potency of hexahydro-diphenidol and hexahydro-sila-diphenidol at the three subtypes was influenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. Indeed, the tertiary analogues hexahydro-diphenidol (HHD) and hexahydro-sila-diphenidol (HHSiD) had an M1 = glandular/smooth muscle greater than cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M1 preferring (M1 greater than glandular/smooth muscle, cardiac).

Animals↗
PubMed1989

Pharmacology of hexahydro-difenidol, hexahydro-sila-difenidol and related selective muscarinic antagonists.

A series of hexahydro-difenidol (HHD) and hexahydro-sila-difenidol (HHSiD) analogues modified in the amino group, the phenyl ring and in the alkylene chain were investigated for their binding and functional properties at muscarinic M1, M2 and M3 receptors. Novel muscarinic receptor antagonists were obtained which exhibited different receptor selectivity profiles from the parent compounds HHD and HHSiD (M1 congruent to M3 greater than M2), e.g. HHD and HHSiD methiodides, M1 greater than M2 congruent to M3; p-fluoro-HHSiD, M3 greater than M1 greater than M2; trans-hexbutenol, M1 greater than M3 greater than M2; and (s)-p-fluoro-hexbutinol, M3 greater than M2 congruent to M1. Stereoselectivity ratios [(R)/(S)] for the enantiomers of HHD, hexbutinol and p-fluoro-hexbutinol were highest at M1, intermediate at M3 and lowest at M2 receptors.

Animals↗
PubMed1989

Stereoselectivity of the interaction of muscarinic antagonists with their receptors.

The stereoselectivity of the interaction with muscarinic receptors of enantiomers of a series of chiral antagonists is receptor subtype dependent. There is no overall relationship between stereoselectivity and receptor affinity. Depending on the antagonist studied, receptor stereoselectivity may indeed reflect: (1) the weakening or loss of a single interaction involving one of the four groups bound to the asymmetric carbon; (2) steric hindrance preventing optimum interaction of the low affinity steroisomer with the receptor; and/or (3) the inversion of the relative positions of two moieties of the ligand with similar structural and electronic properties i.e. comparable affinities for the two corresponding subsites in the receptor.

Animals↗
PubMed1988

Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M1-type.

The present study was designed to further characterize the presynaptic muscarinic M1-receptor responsible for the inhibition of neurogenic contractions in the isolated rabbit vas deferens. Electrically induced twitch contractions of this preparation were inhibited by the M1-agonist, McN-A-343, and by some of its analogs: 4-chloro-phenyl derivative greater than McN-A-343 greater than trans-olefinic analog greater than cis-olefinic analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M1-receptors in sympathetic ganglia. A highly significant correlation was found between the antimuscarinic potencies of atropine, pirenzepine and a series of 9 antagonists structurally related to the ganglionic M1 beta-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the McN-A-343-induced inhibition of twitch contractions in rabbit vas deferens or the muscarine-induced depolarization in rat isolated superior cervical ganglia. It is suggested that the presynaptic muscarinic receptor that mediates inhibition of neurogenic contractions in rabbit vas deferens is of the ganglionic M1 beta-type.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1988

Stereoselectivity of the enantiomers of trihexyphenidyl and its methiodide at muscarinic receptor subtypes.

High stereoselectivity was observed for the enantiomers of trihexyphenidyl and trihexyphenidyl methiodide at muscarinic M1-receptors in field-stimulated rabbit vas deferens and at M2 alpha- and M2 beta-receptors in guinea-pig atrium and ileum, respectively. Considerably higher affinities (up to 1700-fold) were found for the (R)-(-)-enantiomers. The stereochemical demands made by the muscarinic receptor subtypes were most stringent at the M1-receptors. The (R)-(-)-enantiomers were found to be potent M1-selective antagonists (pA2 = 10.1/10.6). They showed a 91- and 45-fold selectivity for M1- over M2 alpha-receptors, respectively.

Animals↗
PubMed1988

Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo.

The antimuscarinic effects of methoctramine (N, N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, 8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 micrograms/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized an pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i.v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2 alpha receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2 alpha receptors.

Animals↗
PubMed1988

Different binding properties of muscarinic M2-receptor subtypes for agonists and antagonists in porcine gastric smooth muscle and mucosa.

The hypothesis that muscarinic receptors on smooth muscle differ from those in epithelial glands was tested by comparing the properties of muscarinic binding sites in porcine fundic smooth muscle with those in mucosal membranes. The binding of agonists and of antagonists was assessed by displacement of [3H]N-methylscopolamine. Pirenzepine (M1-antagonist) labeled low-affinity binding sites in smooth muscle (KD = 229 nM) and in mucosa (KD = 124 nM) consistent with the presence of M2 sites. Carbachol interacted with a high-affinity (KD = 164 nM) and a low-affinity (KD = 18.2 microM) state of binding sites in smooth muscle. Guanyl 5'-yl-imidodiphosphate converted all sites to the low-affinity state. N-ethylmaleimide pretreatment increased the affinity of carbachol and the proportion of high-affinity sites. In clear contrast, only low-affinity sites of carbachol were detectable in mucosa (KD = 17 microM) that were not modulated by N-ethylmaleimide or guanyl 5'-yl-imidodiphosphate. The cardioselective antagonist AF-DX 116 displayed low affinity to mucosal binding sites (KD = 3.4 microM), whereas its affinity to smooth muscle was 503 nM. The antagonist hexahydro-sila-difenidol had a very high affinity (KD = 2.9 nM) to mucosal receptors, whereas its affinity to smooth muscle sites was 88 nM. These data show that muscarinic M2 binding sites in mucosa and smooth muscle can be distinguished by both agonist and antagonist binding experiments, and suggest the existence of different subtypes of M2-binding sites in these tissues.

Animals↗
PubMed1988

Contribution of M2 alpha and M2 beta muscarinic receptors to the action of cholinergic stimuli on prostaglandin synthesis and mechanical function in the isolated rabbit heart.

This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H- pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M2 alpha antagonist, and hexahydro-sila-difenidol (HHSiD), an M2 beta antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M2 alpha and M2 beta subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M2 beta, whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M2 alpha muscarinic receptors.

Acetylcholine↗
PubMed1987

Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine.

The antimuscarinic effects of methoctramine (N,N'-bis[6- [(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine tetrahydrochloride) were investigated in vitro in isolated paced left (force) and spontaneously beating right (force and rate) atria of guinea pigs as well as ileum of guinea pig and rat. Methoctramine was a potent competitive antagonist of M-2 muscarinic receptors in myocardium and pacemaker cells over a wide range of concentrations. The pA2 values ranged from 7.74 to 7.93. They were not significantly different in the two cardiac preparations and were independent of the agonist used (muscarine and carbachol). A combination of methoctramine with atropine resulted in addition of the dose ratios for left atria, which is expected for two antagonists interacting competitively with the same receptor site. In contrast, a combination of methoctramine with gallamine produced a less than additive shift of the dose-response curve for carbachol, confirming that gallamine acts as an allosteric antagonist at cardiac muscarinic receptors. Methoctramine was 54 to 132-fold less potent in ileal than in atrial preparations (pA2 values ranging from 5.81 to 6.20) which makes it the most cardioselective antimuscarinic agent now available. A combination of methoctramine with atropine gave a slight supra-additive antagonism on guinea pig ileum, which suggests that methoctramine interacts to some extent with a second independent site. These results strongly reinforce the view that M-2 muscarinic receptors are not a homogeneous population.

Animals↗
PubMed1987

Selective blockade in vivo of cardiac muscarinic M2 receptors by a polymethylene tetramine, BHC-9C.

The antimuscarinic effects of BHC-9C (N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1,9-nonanediamine tetrahydrochloride), a member of a series of polymethylene tetraamines with unprecedented in vitro selectivity for cardiac muscarinic M2 receptors, were assessed in several in vivo test systems. BHC-9C (300 micrograms/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat. In contrast, it displayed no considerable blocking activity at vascular M2 receptors subserving vasodepression and at ganglionic M1 receptors that mediate cardiovascular stimulation in the anaesthetized and pithed rat, respectively. These in vivo data are consistent with the suggestion based on in vitro experiments that BHC-9C is a highly selective antagonist of cardiac muscarinic M2 receptors.

Anesthesia↗