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D J Triggle

Publications and source records attributed to D J Triggle.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations.

The pharmacological, radioligand binding, and electrophysiological properties of FPL 64176, a new nondihydropyridine Ca2+ channel activator, were studied in rat tail artery, cardiac membranes, and A7r5 smooth muscle cells. FPL 64176 induced a contractile response, with an EC50 value of 2.11 x 10(-7) M. The maximum tension response to FPL 64176 was approximately 2-fold higher than that to (S)-Bay K 8644. FPL 64176 showed no significant inhibitory activity at concentrations up to 10(-5) M. The Ca2+ channel antagonists nifedipine, verapamil and diltiazem noncompetitively antagonized and completely relaxed the responses induced by FPL 64176. IC50 values of these three drugs were 5.22 x 10(-9), 1.31 x 10(-7), and 1.95 x 10(-7) M, respectively, for relaxing submaximum contractile responses to FPL 64176 (5 x 10(-7) M). The washout time for FPL 64176 was about 40 min, which was much longer than that for (S)-Bay K 8644 (within 1 min). FPL 64176 weakly inhibited (+)-[3H]PN 200-110, [3H]D888, and [3H]TA-3090 binding in rat cardiac membranes, with IC50 values of 1.04 x 10(-5) M and 7.03 x 10(-6) M for inhibition of (+)-[3H]PN 200-110 and [3H]TA-3090 binding, respectively, and with 23% inhibition of [3H]D888 binding at a FPL 64176 concentration of 1 x 10(-5) M. Dissociation kinetics of the three radioligands were allosterically accelerated by FPL 64176. Electrophysiological studies on the A7r5 smooth muscle cell line directly confirmed a large (approximately 14-fold) stimulatory effect on L-type Ca2+ current amplitude. The results suggest that FPL 64176 is a new type of Ca2+ channel activator with higher efficacy and a mechanism and site of action that are distinct from those for (S)-Bay K 8644.

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

Calcium-channel drugs: structure-function relationships and selectivity of action.

Calcium channels are ubiquitously distributed in excitable cells. The calcium-channel antagonists interact specifically at the L subclass of channels to mediate cardiovascular effects. These channels may be considered as pharmacologic receptors with specific drug binding sites and subject to a variety of regulatory influences. Each site is specific for agents of the three principal structural classes--the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines--and each exhibits defined structure-activity relationships. The 1,4-dihydropyridine structure exhibits both potent antagonistic and activator properties. The calcium channel antagonists exhibit considerable selectivity of action in the cardiovascular system, both between and within structural groups. This selectivity has a variety of causes including voltage dependence of the interaction, whereby the apparent affinity of the antagonist is determined by the membrane potential and stimulus pattern. Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1,4-dihydropyridines is reviewed.

Calcium↗
PubMed1991

Characterization of binding of the ATP-sensitive potassium channel ligand, [3H]glyburide, to neuronal and muscle preparations.

Binding of the hypoglycemic sulfonylurea, [3H]glyburide, to crude membrane fractions from brain, heart and smooth (intestinal) muscle was saturable, linear with protein concentration and reversible. Saturation analysis revealed high affinity sites (KH values, 7 x 10(-11) M, 5 x 10(-11) M and 6 x 10(-11) M), with Bmax-H values 209, 36 and 23 fmol/mg protein in the brain, heart and smooth muscle, respectively. High affinity [3H]glyburide binding was pharmacologically specific, insensitive to a variety of receptor-active ligands, but sensitive to a series of sulfonylureas, and good, essentially 1:1, correlations were obtained between binding affinities and literature-derived pharmacologic activities. The K+ channel activators, cromakalim, nicorandil, pinacidil and minoxidil were not effective as inhibitors of [3H]glyburide binding. However, diazoxide was a modestly effective inhibitor. Putative low affinity sites (KL values, 3 x 10(-7) M, 1 x 10(-7) M and 2 x 10(-9) M) with Bmax-L values 4956, 336 and 53 fmol/mg protein in brain, heart and smooth muscle, respectively, were identified. Their significance remains to be established. Except for ATP gamma S, the ability of nucleotide triphosphates to inhibit high affinity [3H] glyburide binding was dependent on the presence of Mg++. ADP, in the presence of Mg++, inhibited binding with an IC50 value of 6.3 x 10(-4) M. Nucleotide monophosphates did not inhibit [3H] glyburide binding in the presence or absence of Mg++, whereas in the presence of Mg++, nucleotide triphosphates were equally potent inhibitors of binding. The rank order potency for nucleotide diphosphate inhibition of binding, in the presence of Mg++, is ADP greater than GDP greater than IDP = UDP. In the absence of Mg++, [3H]glyburide binding shows a biphasic response to ADP, and the inhibition of binding by ADP was prevented by ATP. It is suggested that this biphasic response is the result of a second nucleotide binding site.

Adenosine Triphosphate↗
PubMed1990

1,4-Dihydropyridine activators in the tiamdipine series.

The pharmacologic and radioligand binding properties of 5-nitro analogs of the 1,4-dihydropyridine Ca2+ channel antagonist, tiamdipine (2-(2-aminoethylthio)methyl-3-carbomethoxy-5-carbomethoxy-6-m ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine) and its N-formyl derivative have been measured in rat tail artery, guinea pig ileum and rat heart. The enantiomers of both analogs showed activator and antagonist properties, the latter being exhibited at lower concentrations.

Animals↗
PubMed1990

Irreversible modification of the voltage-sensitive calcium channel by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) inhibited, in vitro, the specific binding of three structurally distinct L-type Ca2+ channel ligands, (+)[3H]PN 200,110, [3H]desmethoxyverapamil and [3H]cis-diltiazem to guinea pig ileal longitudinal smooth muscle. Maximum tension responses to Ca2+ in a K(+)-depolarized functional smooth muscle preparation were reduced in a concentration-dependent manner following pretreatment with EEDQ and washout. Microsomal membranes prepared from smooth muscle pretreated with EEDQ followed by extensive washout showed a significant reduction in the amount of (+)[3H]PN 200,110 bound without change of ligand affinity. Similar results were obtained in cardiac ventricle microsomes. Preincubation with verapamil (1 x 10(-5) M) largely prevented this reduction in [3H]PN 200,110 binding sites by EEDQ. 45Ca2+ uptake in cortical synaptosomes during 1-sec depolarization following 68.5 mM K+ was also inhibited by EEDQ. Specific binding of [125I]omega-conotoxin GVIA to rat cerebral cortex membranes was inhibited by EEDQ, also in an apparently irreversible manner as seen by the marked reduction in binding site density with no significant change in the KD value. These observations indicate that EEDQ blocks Ca2+ channel function and reduces irreversibly both 1,4-dihydropyridine and omega-conotoxin GVIA binding sites.

Adrenergic alpha-Antagonists↗
PubMed1990

Receptor model for the molecular basis of tissue selectivity of 1, 4-dihydropyridine calcium channel drugs.

Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate ] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the alpha 1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from other reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltage-sensing alpha-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S 'reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate ] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.

Amino Acid Sequence↗
PubMed1990

New ligands for L-type Ca2+ channels.

Although the clinically important categories of drug represented by verapamil, nifedipine and diltiazem are defined as acting at three major and discrete sites on the L class of voltage-dependent Ca2+ channel, it is likely that some new classes of drug modulate channel activity by acting at additional sites. David Rampe and David Triggle describe the actions of some of these new drugs, which may both offer improved therapeutic and side-effect profiles over existing agents and provide information to define further the structure and function of this channel class. These drugs may mimic the actions of endogenous ligand(s) and such ligands could provide new directions for Ca2+ channel drug structures.

Animals↗
PubMed1990

4-Isoxazolyl-1,4-dihydropyridines: biological, theoretical, and structural studies.

Biological activity was determined for a series of seven isoxazolyldihydropyridines (IDHPs). The highest biological activity was observed for 5-alkyl-3-phenyl-IDHP (1), for which the O-endo conformation at the ring juncture between the heterocyclic rings is known in the solid state. The 3,5-dialkyl-IDHPs were intermediate in overall activity. A theoretical study of rotation about this ring juncture was performed to estimate the relative energy and barrier to rotation for the different conformers as a function of both the ring juncture between the heterocyclic rings and the esters in the 3- and 5-position of the dihydropyridine. Molecular mechanics predicts the minimum energy conformer to be O-exo-ap,ap, while quantum mechanical calculations predict O-exo-sp,sp as the minimum-energy conformer. Both methods indicate that the barrier to rotation about the heterocyclic ring juncture should be relative low, but both methods appear to overestimate the difficulty of ester rotation. A single-crystal X-ray diffractometry study of the (3,5-dimethylisoxazolyl)dihydropyridine 2 was carried out, and shows the O-endo ring juncture and sp,sp ester conformation. 2D NOESY NMR spectroscopy indicates the presence of both conformations about the ring juncture, at room temperature, as evidenced by correlations for both alkyl groups on the isoxazole with the C-2 methyl on the DHP moiety. The ap ester conformer was also evidenced by NOESY, indicating that ester interconversion must take place.

Animals↗
PubMed1990

Calcium, calcium channels, and calcium channel antagonists.

Voltage-dependent Ca2+ channels are an important pathway for Ca2+ influx in excitable cells. They also represent an important site of action for a therapeutic group of agents, the Ca2+ channel antagonists. These drugs enjoy considerable use in the cardiovascular area including angina, some arrhythmias, hypertension, and peripheral vascular disorders. The voltage-dependent Ca2+ channels exist in a number of subclasses characterized by electrophysiologic, permeation, and pharmacologic criteria. The Ca2+ channel antagonists, including verapamil, nifedipine, and diltiazem, serve to characterize the L channel class. This channel class has been characterized as a pharmacologic receptor, since it possesses specific drug-binding sites for both antagonists and activators and it is regulated by homologous and heterologous influences. The Ca2+ channels of both voltage- and ligand-regulated classes are likely to continue to be major research targets for new drug design and action.

Animals↗
PubMed1990

Calcium antagonists. History and perspective.

The calcium channel antagonists are a heterogeneous group of drugs acting on one class of voltage-dependent channel. Their modes and sites of actions are reviewed in this historical perspective and placed in the context of the cellular events underlying homeostasis. Calcium channel antagonists should be regarded as a subset of a larger family of Ca2+ modulators, agents that block or activate functions at a variety of control loci for Ca2+ homeostasis. In a number of important respects, the Ca2+ channel may be viewed as a pharmacologic receptor that defines the existence of specific drug binding sites and their regulation by homologous and heterologous influences. We describe the factors that define the selectivity of action of channel antagonists, with particular emphasis on state-dependent interactions controlled by voltage-modulated drug interactions, and discuss future developments in Ca2+ channel ligands, emphasizing the contributions of molecular biology and the development of more specific and selective agents.

Animals↗
PubMed1989

Homologous regulation of voltage-dependent calcium channels by 1,4-dihydropyridines.

Chronic treatment of PC 12 cells with the 1,4-dihydropyridine Ca2+ channel antagonist nifedipine [5 x 10-8M/5 days] and the activator S Bay K 8644 [5 x 10-7 M/5 days] resulted in up- and down-regulation of 1,4-dihydropyridine binding site density by 29 and 24%, respectively, without change in affinity. These changes in binding site density represent functional changes as indicated by the corresponding changes in K+ depolarization-induced 45Ca2+ uptake and in whole cell currents carried by Ba2+ ions. This homologous regulation of voltage-dependent Ca2+ channels [VDCC] by potent and specific ligands parallels that observed for other classes of membrane receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Binding of A 1,4-dihydropyridine calcium channel activator, (-) S Bay K 8644, to cardiac preparations.

The 1,4-dihydropyridine Ca2+ channel activator, (-) [3H]Bay K 8644, binds to cardiac membranes and polarized [5 mM K+] and depolarized [50 mM K+] cardiac cells. Binding to microsomal membranes at 25 degrees C indicates a single set of binding sites, KD = 2.9 x 10(-9) M and a site density, 337 fmoles/mg protein, not different from that measured by antagonist 1,4-dihydropyridines. Binding to neonatal rat myocytes at 37 degrees C was independent of membrane potential with a KD value of 5 x 10(-8)M and a site density, 63 fmoles/mg protein, not significantly different from that measured by PN 200 110. These results indicate that 1,4-dihydropyridine activators and antagonists label the same number of binding sites in cardiac tissue, but that activator binding to intact myocytes is voltage-independent.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

1,4-Dihydropyridine activators and antagonists: structural and functional distinctions.

The dihydropyridine series of drugs contains both potent antagonists and potent activators of Ca2+ channels. The structural differences between antagonists and activators are small and, indeed, activators can behave as antagonists at high levels of membrane depolarization. Here, David Triggle and David Rampe describe recent insights into the factors--including structure of the drug and activation state of the channel--that influence the behavior of these drugs, and discuss models that have been proposed to describe their mechanism of action.

Animals↗