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D J Triggle

Publications and source records attributed to D J Triggle.

At least 55 records · Page 3Linked to original sources
PubMed1992

Synthesis of 2-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo [3.2.1]octanes and 2 alpha-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-enes as potential muscarinic agonists.

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [3H]QNB and [3H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10(-6) and 1.79 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10(-4) M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo- [3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.

Animals↗
PubMed1992

Pharmacologic and radioligand binding studies of 1,4-dihydropyridines in rat cardiac and vascular preparations: stereoselectivity and voltage dependence of antagonist and activator interactions.

The pharmacologic and radioligand-binding properties of 1,4-dihydropyridines in an activator (Bay K 8644) and an antagonist (nifedipine) series were studied in rat tail artery, heart membrane, and neonatal rat ventricular myocytes. The S-enantiomers of the activator series contracted rat tail artery in the presence of 15 mM K+ (EC50 values of 10(-8) to 10(-5) M). (S)-Bay K 8644 (I) and its o-difluoromethoxy analog (III) were the most potent members of the activator series examined. The abilities of the activators to stimulate maximum tension response of the artery differed with structure; thus, the efficacy of (S)-Bay K 8644 was 70% that of the analog lacking the 3-carbomethoxy group. The R-enantiomers of the activator series and a series of achiral nifedipine analogs were inhibitory in the same tissue. The intact-cell binding assay revealed the binding affinities of 1,4-dihydropyridine antagonists in depolarized cells (50 mM K+) to be higher than those in polarized cells (5 mM K+). The ratio KD (polarized)/KD (depolarized) was 77 for nifedipine (IC50 = 5.4 x 10(-9) M) but was only 2.9 for the weak 3-methoxy nifedipine analog (IC50 = 4.8 x 10(-6) M); an approximately linear relationship exists between this ratio and the antagonist potency. In marked contrast, and in confirmation of previous work [Mol. Pharmacol. 35:541-552 (1989)], the binding affinities of activators were not significantly affected by membrane potential, regardless of potency. We conclude that the S-enantiomers of Bay K 8644 analogs are activators with different potency and efficacy and that the R-enantiomers are antagonists, that the binding of 1,4-dihydropyridine antagonists is voltage dependent, whereas binding of the activators is not, and that the voltage-dependence of binding of the antagonists is correlated with the potency of the antagonist.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

QSAR, diagnostic statistics and molecular modelling of 1,4-dihydropyridine calcium antagonists: a difficult road ahead.

Quantitative structure-activity relationships of a series of substituted 1,4-dihydropyridine calcium channel antagonists were studied. The analysis is difficult because of the problem of multicollinearity of substituent parameters, a high-leverage point, and position-dependent grouped observations. Canonical regression appears to be the method of choice. With respect to a maximum activity, it was shown that the following rank order of substituent parameters exists: Lipophilicity approximately ortho-position > inductivity > minimum width > meta-position. The molecular conformation of antagonists does not differ markedly (with exception of nifedipine derivatives and nimodipine), but differences seem to exist between the antagonists and the activator BAY K 8644.

Animals↗
PubMed1991

Thermodynamic and kinetic aspects of agonist and antagonist binding to 1,4-dihydropyridine receptors.

The kinetic and equilibrium binding properties of the 1,4-dihydropyridine activator [3H](-)-S-Bay K 8644 and the antagonist [3H](+)-PN 200-110 were determined in rat heart membrane particulate preparations at temperatures between 4 and 37 degrees C. The binding of [3H](-)-S-Bay K 8644 was temperature-dependent with a single binding site with KD = 3.57 nM and Bmax = 330 fmol/mg.protein at 25 degrees C. The association and dissociation rate constants were 3.4 x 10(7) min-1 M-1 and 0.095 min-1 respectively at 25 degrees C and decreased slightly at lower temperatures. In contrast, [3H](+)-PN 200-110 bound to high (KD(H) = 0.032 nM, Bmax(H) = 316 fmol/mg.protein) and low affinity sites (KD(L) = 27.6 nM and Bmax(L) = 6432 fmol/mg.protein) at 25 degrees C in rat heart preparation. A similar two-site binding of [3H](+)-PN 200-110 was found in rat brain preparation, but only a single binding site was detected in rat skeletal muscle. Binding of [3H](+)-PN 200-110 to the high and low affinity sites in cardiac membranes was sensitive and insensitive respectively to temperature. Association and dissociation rates of [3H](+)-PN 200-110 at the high affinity binding sites were best fitted as mono-exponential functions. Association and dissociation rates of [3H](+)-PN 200-110 were 3.94 x 10(8) min-1 M-1 and 7.86 x 10(-3) min-1 at 25 degrees C. The association rate varied only slightly (3-fold), but the rate of dissociation decreased significantly (200-fold) with temperature from 37 to 4 degrees C. Thermodynamic analysis of equilibrium binding showed that the binding of activator was enthalpy driven, whereas the binding of antagonist to the high affinity site was both entropy- and enthalpy-driven and to the low affinity site was totally entropy-driven.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Interactions of local anesthetics with neuronal 1,4-dihydropyridine binding sites.

A series of local anesthetics competed with 1,4-dihydropyridine [3H]PN 200,110 binding to synaptosomes from guinea pig cerebral cortex synaptosomes. Dibucaine (10(-3)M) increased the dissociation rate of bound [3H]PN 200,110 consistent with an indirect, rather than competitive, interaction between local anesthetics and the 1,4-dihydropyridine site. The binding activities were compared to those previously available for local anesthetic competition with [3H]batrachotoxinin benzoate binding at a Na+ channel site. A linear correlation was observed between the two sets of activities with significantly higher activities being exhibited at the Na+ channel site. This relationship is consistent with the significant structural homologies exhibited between Na+ and Ca2+ channels.

Anesthetics, Local↗
PubMed1991

Interactions of analogs of the 1,4-dihydropyridine tiamdipine in cardiac and smooth muscle.

Two series of 1,4-dihydropyridines related to tiamdipine, 2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6- methyl-4-(3-nitrophenyl)-1,4-dihydropyridine, have been evaluated for their pharmacologic and radioligand binding properties in smooth and cardiac muscle. In the tiamdipine series the influence of phenyl ring substitution, 3-Cl, 3-MeO and 3-CF3, was greatly reduced relative to the N-formyl and neutral nifedipine derivatives. Consistent with our previous observations onset and offset of action were greatly reduced by the presence of the amine side chain. In tiamdipine analogs also bearing an asymmetric substituent at C-2, chirality at C-4 was determinant for activity.

Animals↗
PubMed1991

Chiral aspects of drug action at ion channels: a commentary on the stereoselectivity of drug actions at voltage-gated ion channels with particular reference to verapamil actions at the Ca2+ channel.

Ion channels may be considered as pharmacological receptors possessing specific drug binding sites with defined structure-activity relationships. Accordingly drug binding to ion channels is stereoselective. Interpretation of this stereoselectivity may be complex because of the existence of differences in affinity and access to different channel states. Such state-dependent interactions may give rise to quantitative and qualitative differences in stereoselectivity. The implications of such differences are reviewed for drug action at Na+, K+ and Ca2+ channels. Detailed attention is paid to the actions of verapamil enantiomers in the cardiovascular system where activities differ in vascular and cardiac tissues because of state-dependent interactions and stereoselective first-oass metabolism.

Animals↗
PubMed1991

Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor.

Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxy lat e], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5- carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxy lat e] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within +/- 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca2+ channel and its ability to accommodate both antagonist and activator ligands.

Calcium Channel Agonists↗
PubMed1991

Age related changes in Ca2+ channels in spontaneously hypertensive rats.

1. The binding of the Ca2+ channel antagonist [3H]PN200 110 to 1,4-dihydropyridine binding sites in cardiac, brain and vascular smooth muscle preparations from WKY and SHR was studied as a function of age and blood pressure. 2. Binding site density in the heart from prehypertensive SHR (6 weeks) was significantly lower than that of WKY. 3. Between 6 and 12 weeks binding site density in SHR increased and between 12 and 24 weeks there was no difference between WKY and SHR. No changes in affinity occurred. 4. In brain a significant fall in binding site density occurred between 6 and 12 weeks and there was (with limited data) an increase in binding site density in tail artery membranes. 5. A good correlation (r = 0.82) exists between blood pressure and cardiac binding site density between 6 and 12 weeks of age in SHR.

Aging↗
PubMed1991

Effects of Ca2+ channel ligands on [3H]QNB binding at m1 and m3 muscarinic receptors.

1. The effects of Ca2+ channel ligands on [3H]QNB binding in m1- or m3-transfected Chinese hamster ovary (CHO) cells have been studied. 2. The IC50 values of Ca2+ channel ligands for the inhibition of [3H]QNB binding were between 10(-6) and 10(-4) M and the rank order of potency was HOE 166 greater than McN 6186 greater than nicardipine greater than tiamdipine greater than verapamil greater than diltiazem greater than Bay K 8644 greater than nifedipine at m1 and m3 receptors. 3. The results indicate that Ca2+ channel ligands employed in this experiment do not distinguish subtypes of muscarinic receptors.

Animals↗
PubMed1991

Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.

The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identified by molecular-mechanics calculations. A comparison of azaprophen and atropine radioligand binding in guinea pig ileum, rat heart, rat brain, and in CHO cells expressing transfected m1 and m3 receptors was conducted. Azaprophen is more active than atropine in all preparations except the m3 receptor expressed in CHO cells. However, like atropine, it does not provide major discrimination among the muscarinic receptor subtypes.

Animals↗
PubMed1991

Synthesis, molecular modeling studies, and muscarinic receptor activity of azaprophen analogues.

Synthesis, radioligand binding, and pharmacologic activities of a series of muscarinic receptor ligands including and related to azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate, 1) have been measured to determine activity and selectivity for muscarinic receptor subtypes. Pharmacologic affinities of antagonists were determined as pA2 values for antagonism of methacholine-induced tension responses in guinea pig ileum. Binding affinities were measured by competition against [3H]QNB binding in guinea pig ileum, rat heart and brain, and m1- or m3-transfected Chinese hamster ovary (CHO) cells. The efficacies of muscarinic agonists in brain were determined by the ratio of binding affinities against [3H]QNB or [3H]NMS and [3H]oxotremorine-M ([3H]Oxo-M). Nine muscarinic antagonists, including azaprophen, did not discriminate significantly between the subtypes of muscarinic receptors. KI values for receptor binding for azaprophen (1) were between 8.81 x 10(-11) and 4.72 x 10(-10) M in ileum, heart, brain, and m1- or m3-transfected CHO cells. The alpha- and beta-benzilate esters 5 and 6 are as potent as azaprophen, and diphenylacetate esters 3 and 4 and N-(6)-benzyl alpha-isomer 7 are less potent than azaprophen. Significant stereoselectivity was exhibited with (+)-azaprophen being approximately 200 times more potent than the (-)-enantiomers and the 3 beta-ol isomer 2 being ca. 50 times less potent than azaprophen in all systems. A molecular modeling-molecular mechanics study was conducted to account for the difference. Putative muscarinic agonists (analogues and isomers of 6-methyl-6-azabicyclo[3.2.1]octan-3-ol acetate) did not discriminate muscarinic receptor subtypes with KI values between 2.77 x 10(-6) and 4.33 x 10(-5) M without significant stereoselectivity in the systems examined. The most active analogue was (1R,3R,5S)-6-[1(R)-phenylethyl]-6-azabicyclo[3.2.1]octan-3 alpha-ol acetate. However, efficacies of these putative agonists were in general very low.

Animals↗
PubMed1991

Sites, mechanisms of action, and differentiation of calcium channel antagonists.

The calcium channel antagonists are a chemically heterogeneous group of agents that includes verapamil, nifedipine, and diltiazem as first-generation agents. They owe their effectiveness to interactions at specific sites associated with a major protein of the L class of voltage-gated channel. The calcium channel may be viewed as a pharmacologic receptor, with specific sites for activator and antagonist ligands that are linked to the functional machinery of the channel. These sites are subject to homologous and heterologous regulation and a number of disease states--both experimental and clinical--alter their expression. The selective actions of these agents are reviewed from several perspectives, particularly that of voltage-dependent interactions that distinguish between cells according to membrane potential and other factors.

Animals↗
PubMed1991

Iminodipropionitrile-induced dyskinesia in mice: striatal calcium channel changes and sensitivity to calcium channel antagonists.

Administration of 3,3'-iminodipropionitrile (IDPN) (1 g/kg, i.p. for 3 days) in mice leads to the development of a characteristic syndrome consisting of lateral and vertical head and neck movements, hyperactivity, random circling, increased locomotor activity, and increased startle response. Nifedipine, verapamil, and diltiazem (10 mg/kg) inhibited significantly the symptoms of IDPN-induced dyskinesia. However, there was no change in the affinity (KD) or the density of PN 200-110 binding sites (Bmax) in whole brains of IDPN-treated mice. Similarly, the K(+)-depolarization-dependent Ca2+ uptake in synaptosomes from whole brain, cortex, or striatum was not altered following IDPN treatment. However, IDPN caused a significant increase in the Bmax value (from 157 +/- 7 fmol/mg to 237 +/- 31 fmol/mg in control and treated groups, respectively) of PN 200-110 binding to the striatum without change of KD value (38 +/- 4.7 pM versus 33 +/- 1.6 pM). IDPN also caused a slight but significant decrease in the KD value (from 68 +/- 10.1 pM to 45 +/- 4.5 pM in control and treated groups, respectively), without significant change of Bmax value (563 +/- 51 fmol/mg versus 485 +/- 41 fmol/mg) of PN 200-110 binding to the cortex. IDPN did not alter omega-conotoxin binding in whole brain, striatum, or cortex. The behavioral effects of chronic IDPN treatment as inhibited by L-type calcium channel antagonists and this may be associated with the observed increase in striatal L-type calcium channels.

Animals↗
PubMed1991

The effects of chronic depolarization on L-type 1,4-dihydropyridine-sensitive, voltage-dependent Ca2+ channels in chick neural retina and rat cardiac cells.

Chick neural retina cells contain functional L-type voltage-dependent Ca2+ channels sensitive to 1,4-dihydropyridines. To investigate the effects of chronic depolarization, cells were grown in medium containing elevated K+. After 4-h to 4-day treatments with elevated K+ (12-73 mM), there was a concentration-dependent decrease in high affinity [3H]PN200-110 binding. Saturation analysis of cells treated for 4 days with 40 mM K+ showed a reduction in maximum ligand binding with no change in affinity. Control and experimental Bmax values were 70.7 +/- 6.4 and 42.2 +/- 4.5 fmol/mg protein, respectively, and control and experimental KD values were 70.2 +/- 7.4 and 68.6 +/- 7.4 x 10(-12) M. The effect of chronic depolarization was time-dependent, reversible, and without effect on cellular protein content. Reduction in 45Ca2+ uptake following chronic depolarization correlated well with the reduction in [3H]PN200-110 binding. The calcium ionophore A23187, 10(-6) M for 24 h, also decreased the binding site density. The calcium channel antagonist D600 had no effect alone on [3H]PN200-110 binding; however, D600 blocked the down-regulation of calcium channels induced by chronic depolarization. The mechanism for Ca2+ channel down-regulation may involve calcium entry, since the effect was blocked by D600 and mimicked by the calcium ionophore A23187. Chronic depolarization with either elevated K+ or veratridine, or chronic treatment with A23187 had no effect on calcium channels in rat neonatal ventricular myocytes, although these cells express functional channels of the 1,4-dihydropyridine-sensitive class.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Regulation of K+ and Ca2+ channels in experimental cardiac failure.

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

Animals↗