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G Lambrecht

Publications and source records attributed to G Lambrecht.

At least 55 records · Page 3Linked to original sources
PubMed1994

Investigation of the actions of PPADS, a novel P2x-purinoceptor antagonist, in the guinea-pig isolated vas deferens.

1. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) was investigated for its ability to act as an antagonist at P2x-purinoceptors which mediate neurogenic excitatory junction potentials (e.j.ps) and contractions in the guinea-pig isolated vas deferens. 2. PPADS (10(-7) M) caused a small potentiation of the phasic, predominantly purinergic component of contractions evoked by symapthetic nerve stimulation, but higher concentrations of PPADS (3 x 10(-6)-3 x 10(-5) M) elicited a substantial and significant concentration-dependent inhibition. In contrast, over the same concentration-range, PPADS had no effect on the tonic, predominantly noradrenergic phase. 3 PPADS (3 x 10(-5) M) also inhibited contractile responses to exogenous alpha,beta-methyleneATP (10(-8)-10(-3)M), a P2x-purinoceptor agonist, without affecting the responses to exogenous noradrenaline (10(-8)-10(-3) M), carbachol (10(-5) M) or histamine (10(-4) M). 4. PPADS (10(-7)-3 x 10(-5) M) produced a concentration-dependent reduction in e.j.p. magnitude and resting membrane potential. The maximum effect was seen at 10(-5) M PPADS, which reduced e.j.p. magnitude from 13.7 +/- 0.6 mV (n = 12) to 1.8 +/- 0.7 mV (n = 12) and membrane potential from -64.8 +/- 0.6 mV (n = 51) to -55.0 +/- 1.8 mV (n = 12). 5. The PPADS-induced depolarization was not inhibited by the P2x-purinoceptor antagonist, suramin (10(-4) M). This indicates that the depolarization was not due to an agonist action of PPADS at P2x-purinoceptors. 6. The results support the proposal that PPADS is a selective antagonist at P2x purinoceptors as opposed to non-P2-purinoceptors in the guinea-pig vas deferens, but its ability to cause membrane depolarization independently of P2x-purinoceptors and also, at a low concentration, to potentiate the phasic component of the neurogenic contraction indicates that it has other actions.

Adenosine Triphosphate↗
PubMed1994

Selective antagonism by PPADS at P2X-purinoceptors in rabbit isolated blood vessels.

1. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), a P2-purinoceptor antagonist, was investigated for its ability to antagonize: (1) P2X-purinoceptor-mediated contractions of the rabbit central ear artery and saphenous artery evoked by either alpha,beta-methylene ATP (alpha,beta-MeATP) or electrical field stimulation (EFS); (2) P2Y-purinoceptor-mediated relaxations of the rabbit mesenteric artery; (3) endothelium-dependent and endothelium-independent, P2Y-purinoceptor-mediated relaxations of the rabbit aorta. 2. alpha,beta-MeATP (0.1-100 microM) caused concentration-dependent contractions of the rabbit ear and saphenous arteries. The negative log[alpha,beta-MeATP] that produced a contraction equivalent to the EC25 for noradrenaline (ear artery) or histamine (saphenous artery) in the absence of PPADS was 6.60 +/- 0.18 (9) and 6.18 +/- 0.17 (9) in the ear artery and saphenous artery, respectively. These effects of exogenous alpha,beta-MeATP were concentration-dependently inhibited by PPADS (1-30 microM). In the ear artery, the negative log[alpha,beta-MeATP] producing a contractile response equivalent to the EC25 of noradrenaline, in the presence of PPADS at 1, 3 and 10 microM was 6.16 +/- 0.18 (8), 5.90 +/- 0.18 (8) and 4.72 +/- 0.36 (8), respectively (P < 0.01). In the saphenous artery, the negative log[alpha,beta-MeATP] values equivalent to the EC25 for histamine in the presence of PPADS at concentrations of 1, 3, 10 and 30 microM were 5.90 +/- 0.19 (8), 5.73 +/- 0.16 (8), 4.99 +/- 0.14 (8) and 4.51 +/- 0.13 (8), respectively (P < 0.01). 3. PPADS at a concentration of 1 microM had no effect on contractions of the ear artery evoked by EFS (4-64 Hz; 1 microM phentolamine present). At higher concentrations (3-30 MicroM) it caused concentration dependent inhibition of neurogenic contractions. In the saphenous artery, PPADS (1-30 MicroM) concentration-dependently inhibited contractions evoked by EFS at frequencies of 4, 8 and 16 Hz. Contractions evoked by EFS at frequencies of 32 and 64 Hz were significantly inhibited by PPADS only at concentrations of 10 and 30 MicroM.4. PPADS (30 MicroM) had no effect on relaxations to 2-methylthio ATP (3 nM-3 MicroM) in rabbit mesenteric artery and to ATP (1 MicroM-I mM) in rabbit aorta (with endothelium intact or removed). In addition,PPADS (30 MicroM) had no significant influence on the contractile potency of noradrenaline and histamine in rabbit ear and saphenous artery, respectively.5. In conclusion, these results support the evidence that PPADS is a selective antagonist of P2X-purinoceptor-mediated responses.

Adenosine Triphosphate↗
PubMed1994

Vasoconstrictor and vasodilator responses to various agonists in the rat perfused mesenteric arterial bed: selective inhibition by PPADS of contractions mediated via P2x-purinoceptors.

1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on vasoconstrictor and/or vasodilator responses to various agonists and electrical field stimulation was investigated in the rat mesenteric arterial bed at basal tone and at tone raised by methoxamine (15-50 microM). 2. At basal tone, nucleotides produced vasoconstriction with the following rank order of potency: alpha,beta-methylene ATP >> 2-methylthio ATP > or = ATP = UTP. PPADS (0.3-10 microM) concentration-dependently antagonized alpha, beta-methylene ATP-, 2-methylthio ATP- and ATP-induced responses. UTP-, noradrenaline- and nerve-mediated (4-32 Hz) increases in perfusion pressure remained unaffected by 10 microM PPADS. 3. In raised tone preparations, nucleotides produced vasodilations, their rank order of potency being 2-methylthio ATP > ATP > UTP. Responses to 2-methylthio ATP were slightly antagonized, whereas ATP- and UTP-induced responses remained unaffected by 10 microM PPADS. In addition, acetylcholine- and adenosine-elicited relaxations were not influenced by 10 microM PPADS. 4. The present results confirm the previously described selective P2x antagonism by PPADS, this compound being ineffective at muscarinic M3- and adenosine P1-receptors as well as at alpha 1-adrenoceptors. There was some inhibition of P2y-purinoceptors but at a much higher concentration than required for inhibition of P2x-purinoceptors. 5. In addition, this study provides evidence for the ineffectiveness of PPADS at both vasoconstriction- and vasodilatation-mediating P2u-purinoceptors.

Adenosine Triphosphate↗
PubMed1993

Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney.

The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.

Animals↗
PubMed1993

WAL 2014--a muscarinic agonist with preferential neuron-stimulating properties.

The ability of WAL 2014 to elicit muscarinic responses was investigated in various in vitro and in vivo models. In CHO cells transfected with human m1- or m3- receptor genes, WAL 2014 was clearly more effective in stimulating the M1-mediated PI response. In isolated tissue preparations, WAL 2014 exhibited full agonist properties in the rabbit vas deferens (putative M1 receptor) and behaved like a partial agonist at M2 receptors in the atrium and M3 receptors in the ileum of guinea-pigs. In the pithed rat, in which the increase in blood pressure is mediated through a stimulation of M1 receptors in sympathetic ganglia, WAL 2014 produced a full dose response curve, whereas the reference compounds RS 86 and arecoline exhibited a bell-shaped behaviour. This is in accord with the view that WAL 2014 selectively activates M1 receptors in sympathetic ganglia, whereas conventional agonists in the same dose range stimulate both ganglionic M1 and vascular M3 receptors. The preferential neuron-stimulating properties were confirmed by EEG recording in the rabbit, in which muscarinic activation occurred at doses similar to those for ganglionic stimulation in the pithed rat. On the other hand, higher doses of WAL 2014 were needed to elicit muscarinic effects in peripheral effector organs, i.e. bradycardia, urinary bladder contraction and increase in airway resistance. It is concluded that WAL 2014 due to its preferential neuronal activity is a promising candidate for a cholinergic substitution therapy in Alzheimer's disease.

Animals↗
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↗
PubMed1993

Thermodynamics of antagonist binding to rat muscarinic M2 receptors: antimuscarinics of the pridinol, sila-pridinol, diphenidol and sila-diphenidol type.

1. We studied the effect of temperature on the binding to rat heart M2 muscarinic receptors of antagonists related to the carbon/silicon pairs pridinol/sila-pridinol and diphenidol/sila-diphenidol (including three germanium compounds) and six structurally related pairs of enantiomers [(R)- and (S)-procyclidine, (R)- and (S)-trihexyphenidyl, (R)- and (S)-tricyclamol, (R)- and (S)-trihexyphenidyl methiodide, (R)- and (S)-hexahydro-diphenidol and (R)- and (S)-hexbutinol]. Binding affinities were determined in competition experiments using [3H]-N-methyl-scopolamine chloride as radioligand. The reference drugs were scopolamine and N-methyl-scopolamine bromide. 2. The affinity of the antagonists either increased or decreased with temperature. van't Hoff plots were linear in the 278-310 degrees K temperature range. Binding of all antagonists was entropy driven. Enthalpy changes varied from large negative values (down to -29 kJ mol-1) to large positive values (up to +30 kJ mol-1). 3. (R)-configurated drugs had a 10 to 100 fold greater affinity for M2 receptors than the corresponding (S)-enantiomers. Enthalpy and entropy changes of the respective enantiomers were different but no consistent pattern was observed. 4. When silanols (R3SiOH) were compared to carbinols (R3COH), the affinity increase caused by C/Si exchange varied between 3 and 10 fold for achiral drugs but was negligible in the case of chiral drugs. Silanols induced more favourable enthalpy and less favourable entropy changes than the corresponding carbinols when binding. Organogermanium compounds (R4Ge) when compared to their silicon counterparts (R4Si) showed no significant difference in affinity as well as in enthalpy and entropy changes. 5. Exchange of a cyclohexyl by a phenyl moiety was associated with an increase or a decrease in drug affinity (depending on the absolute configuration in the case of chiral drugs) and generally also with a more favourable enthalpy change and a less favourable entropy change of drug binding. 6. Replacement of a pyrrolidino by a piperidino group and increasing the length of the alkylene chain bridging the amino group and the central carbon or silicon atom were associated with either an increase or a decrease of entropy and enthalpy changes of drug binding. However, there was no clear correlation between these structural variations and the thermodynamic effects. 7. Taken together, these results suggest that hydrogen bond-forming OH groups and, to a lesser extent, polarizable phenyl groups contribute significantly to the thermodynamics of interactions between these classes of muscarinic antagonists and M2 muscarinic receptors.

Animals↗
PubMed1993

PPADS selectively antagonizes P2X-purinoceptor-mediated responses in the rabbit urinary bladder.

1. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), an inhibitor of P2X-purinoceptor-mediated responses in rabbit vas deferens, was investigated for its ability to antagonize contractions evoked by alpha,beta-methylene ATP (alpha,beta-MeATP), carbachol and electrical field stimulation in the rabbit urinary bladder detrusor muscle. 2. PPADS. (1-30 microM) caused concentration-dependent inhibition of contractions to the stable P2X-purinoceptor agonist, alpha,beta-MeATP, decreasing the maximum response to alpha,beta-MeATP (30 microM) at concentrations of 3-30 microM. The pD2 value for alpha,beta-MeATP in the absence of PPADS was 6.52 +/- 0.10 (8). In the presence of PPADS at concentrations of 1, 3, 10 and 30 microM the negative log concentrations of alpha,beta-MeATP that cause the same contractile response as the pD2 value were significantly different from control, being respectively 6.17 +/- 0.09 (8), 5.64 +/- 0.12 (7), 5.15 +/- 0.23 (7) and 4.78 +/- 0.22 (5). 3. PPADS (1-30 microM) caused concentration-dependent inhibition of contractions to stimulation of intramural purinergic nerves (1-32 Hz). There was a greater inhibition at lower frequencies (1-8 Hz) than at higher frequencies (16-32 Hz). PPADS, 30 microM, did not produce significantly greater antagonism than 10 microM. 4. PPADS (30 microM) had no significant influence on the contractile potency of carbachol: the pD2 values of carbachol in the absence and presence of PPADS were not significantly different being 6.42 +/- 0.16 (5) and 6.33 +/- 0.18 (5), respectively. However, PPADS caused a small, but significant, suppression of the maximal response of carbachol, reducing it by approximately 9%. 5. Radioligand binding studies carried out on rabbit bladder membranes with [3H]-alpha,beta-methylene ATP([3H]-alpha,beta-MeATP) showed that PPADS concentration-dependently inhibited the binding of [3H]-alpha,beta-MeATP to P2X-purinoceptors, while the binding of [3H]-quinuclidinyl benzilate to muscarinic cholinoceptors was not affected.6. Thus, PPADS (1-30 microM) antagonized responses mediated via P2X-purinoceptors in the rabbit urinary bladder. It was selective for P2-purinoceptor-mediated contractions rather than those mediated via muscarinic receptors. Binding studies demonstrated that the antagonistic effect of PPADS is via a direct interaction with P2x-purinoceptors.

Adenosine Triphosphate↗
PubMed1992

Histamine H1 receptors mediate vasodilation in guinea-pig ileum resistance vessels: characterization with computer-assisted videomicroscopy and new selective agonists.

Histamine receptors on guinea-pig ileum submucosal arterioles (outside diameter 40-80 microns) were studied in vitro using a computer-assisted videomicroscopy system (Diamtrak). Histamine receptor agonists investigated in this study were histamine, the H1 receptor-selective compound, 2-[2-(3-fluorophenyl)-4-imidazolyl]ethanamine (VZ 20), the H2 receptor-selective compounds, dimaprit, impromidine, (+/-)-N1-[3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (arpromidine) and (+/-)-N1-[3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (BU-E-75), as well as the H3 receptor-selective drug, (R)-alpha-methylhistamine ((R)-alpha-MeHA). Applied to vessels at resting tone, the agonists (1 nM-300 microM) did not change arteriolar diameter. Vessels preconstricted by 10 microM noradrenaline showed similar concentration-dependent vasodilations with histamine and VZ 20 (pD2 = 5.38 and 5.36, respectively). This histamine-induced vasodilation was not affected by tetrodotoxin (0.5 microM) or indomethacin (1 microM), but was completely abolished in the presence of 1 microM of the H1 receptor antagonist, mepyramine. Calculation of the antagonist affinity of mepyramine for the histamine receptors in submucosal arterioles yielded a pA2 of 9.46. In contrast to histamine and VZ 20, the H2 receptor agonist, dimaprit, and the H3 receptor agonist, (R)-alpha-MeHA, were ineffective at preconstricted arterioles. The guanidine-type H2 receptor agonists, impromidine, apromidine and BU-E-75, produced vasodilation at noradrenaline-preconstricted arterioles (-log EC50 = 4.47, 5.30 and 5.39, respectively) but, in contrast to histamine, were ineffective at arterioles preconstricted by U-46619 (300 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Stereoselective interaction of procyclidine, hexahydro-difenidol, hexbutinol and oxyphencyclimine, and of related antagonists, with four muscarinic receptors.

We investigated the binding properties of the (R)- and (S)-enantiomers of the muscarinic antagonists trihexyphenidyl, procyclidine, hexahydro-difenidol, p-fluoro-hexahydro-difenidol, hexbutinol, p-fluoro-hexbutinol, and their corresponding methiodides at muscarinic M1, M2, M3 and M4 receptor subtypes. In addition, binding properties of the (R)- and (S)-enantiomers of oxyphencyclimine were studied. The (R)- enantiomers (eutomers) of all the compounds had a greater affinity than the (S)-isomers for the four muscarinic receptor subtypes. The binding patterns of the (R)- and (S)-enantiomers were generally different. We did not observe any general correlation between the potency of the high-affinity enantiomer and the affinity ratio (eudismic ratio) of the two enantiomers. The results are discussed in terms of a 'four subsites' binding model.

Alkynes↗
PubMed1992

PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses.

We have characterized PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) as a novel antagonist which selectively blocks P2 purinoceptor-mediated responses in rabbit vas deferens at pre- and postjunctional sites. PPADS did not interact with alpha 1-adrenoceptors, muscarinic M2 and M3 receptors, histamine H1 and adenosine A1 receptors. Thus, PPADS is a novel and useful pharmacological tool to study co-transmission in tissues where ATP and co-existing neurotransmitters act in concert.

Adenosine Triphosphate↗
PubMed1992

Characterization of muscarinic receptors mediating vasodilation in guinea-pig ileum submucosal arterioles by the use of computer-assisted videomicroscopy.

Muscarinic receptors of resistance vessels (submucosal arterioles, outside diameter 50-75 microns) from the guinea-pig small intestine were investigated in vitro using a computer-assisted videomicroscopy system (Diamtrak). The muscarinic receptor which mediates vasodilation of precontracted [U-46619 (300 nM) or (-)-noradrenaline (10 microM)] arterioles was characterized with several muscarinic agonists and subtype-selective antagonists. The following agonists all produced equivalent maximum vasodilation (given in rank order of potency): acetylcholine = arecaidine propargyl ester (APE) greater than oxotremorine = (+/-)-muscarine = (+/-)-methacholine greater than carbachol greater than 4-[[N-(4-chlorophenyl)carbamoyl]oxy]-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). 4-[[N-(3-Chlorophenyl)-carbamoyl]oxy]-2-butynyltrimethylammonium chloride (McN-A-343) and N-ethyl-guvacine propargyl ester (NEN-APE) produced minimal or no arteriolar vasodilation. The muscarinic antagonists pirenzepine, (+-)-5,11-dihydro-11-[[[2-[2-((dipropylamino)methyl)-1-piperidinyl] ethyl]amino]-carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AF-DX 384), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AQ-RA 741), p-fluorohexahydro-sila-difenidol (p-F-HHSiD), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and (R)- and (S)-hexahydro-difenidol [(R)-HHD, (S)-HHD] shifted the muscarine, methacholine or carbachol dose-response curve to the right in a competitive manner. Schild analysis of the data yielded pA2 values for pirenzepine (6.74/6.9), AF-DX 384 (6.72), AQ-RA 741 (6.58), p-F-HHSiD (7.53/7.57), 4-DAMP (9.06), (R)-HHD (7.88/8.32) and (S)-HHD (5.52/5.88). Thus, it can be concluded that submucosal arterioles possess only the M3 functional muscarinic receptor, the activation of which causes blood vessel dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Affinity profiles of pizotifen, ketotifen and other tricyclic antimuscarinics at muscarinic receptor subtypes M1, M2 and M3.

The affinity of pizotifen, ketotifen and other tricyclic antimuscarinic drugs for different muscarinic receptor subtypes was investigated in vitro in functional experiments with field-stimulated vas deferens of the rabbit (M1 and M2 receptors) and with ileum and trachea of the guinea-pig (M3 receptors). All compounds were competitive antagonists in the three tissues. Like the close analogue cyproheptadine (pA2 = 7.99-8.08), pizotifen (pA2 = 7.23-7.81) and ketotifen (pA2 = 6.34-6.99) were devoid of selectivity for the receptor subtypes studied. Thiazinamium, although exhibiting high affinity for muscarinic receptors (pA2 = 7.83-8.51), was found to be non-selective. In contrast, the novel pirenzepine analogue nuvenzepine was selective for M1 receptors (pA2 = 6.63-7.74). The lack of selectivity of cyproheptadine, pizotifen and ketotifen is reflected in the chemical structures of these drugs. All three antagonists are composed of a very similar tricyclic ring system linked to a 1-methyl-4-piperidylene ring. The finding that thiazinamium, pizotifen and cyproheptadine were potent muscarinic antagonists and possessed non-selective affinity characteristics may have therapeutic implications.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1992

Cryptolepis sanguinolenta: antimuscarinic properties of cryptolepine and the alkaloid fraction at M1, M2 and M3 receptors.

From an ethanol extract of the roots of Cryptolepis sanguinolenia the alkaloid fraction and its main constituent cryptolepine were isolated by partitioning at pH 11 and column chromatography using silica gel and chloroform/methanol as eluent. Cryptolepine was identified mainly by EI-MS and 1H/13C-NMR spectroscopy. Cryptolepine (3-30 microM) and the alkaloid fraction of Cryptolepis sanguinolenta (3-10 micrograms/ml) antagonized muscarinic effects at M1 receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, and M3 receptors in guinea-pig ileum. The experiments, using N-methylatropine as reference drug, showed a significant antimuscarinic activity for both cryptolepine and the alkaloid fraction, but no appreciable receptor subtype selectivity (pA2 = 5.00-5.73). Cryptolepine was determined as the antimuscarinic principle of Cryptolepis sanguinolenta. At higher concentrations both materials displayed negative inotropic effects.

Alkaloids↗
PubMed1991

Effect of extracellular calcium concentration on potency of muscarinic agonists at M1 and M2 receptors in rabbit vas deferens.

The M1 potency (decrease in neurogenic response) of carbachol, oxotremorine, muscarine, arecaidine propargly ester (APE) and 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343) in rabbit field-stimulated vas deferens (prostatic segments) increased up to 15-fold when calcium was lowered (3.5-1.0 nM). The M2 receptor-mediated increase in twitch height in response to carbachol and the M1 affinity of pirenzepine were independent of calcium concentration (2.5 and 1.0 mM). Thus, prostatic segments of rabbit vas deferens can be used successfully at 1.0 mM calcium to determine M1 potencies of agonists and M1 affinities of antagonists without counteracting stimulation of M2 receptors.

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