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C R Triggle

Publications and source records attributed to C R Triggle.

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

Vasopressin (V1) receptor characteristics in rat aortic smooth muscle cells.

We report saturable, high-affinity, specific, reversible binding sites for both [3H]arginine vasopressin ([3H]AVP) and d(CH2)5Tyr(Me)-[3H]AVP, a V1-selective antagonist, in cultured smooth muscle cells obtained from rat aorta (RA) and rat mesenteric artery (RMA). Specific binding of [3H]AVP had the following characteristics in adherent monolayers of RA and RMA smooth muscle cells: dissociation constant (KD) = 1.42 and 1.23 nM and maximal binding capacity (Bmax) = 9,500 and 29,910 sites/cell, respectively. Lower KD and higher Bmax values were detected for 3H-labeled V1 antagonist binding to both types of cells. Complete dissociation of [3H]-AVP binding to RA cells occurred in a biphasic manner with two rate constants of dissociation, suggesting high- and low-affinity states of the binding site for the agonist interaction. Partial dissociation of the antagonist-specific binding occurred, and it was monophasic, suggesting interaction of the 3H-labeled V1 antagonist radioligand to the high-affinity binding state. Inhibition constant (Ki) values determined by competitive inhibition of [3H]AVP binding to RA cells by a series of AVP-related peptide analogues and antagonists were consistent with the saturation data. AVP in a concentration-dependent manner induced the accumulation of inositol phosphates [mean effective concentration (EC50) 1 nM] in the adherent RA cells. The free cytosolic Ca2+ level in the dispersed RA smooth muscle cells was increased by AVP (EC50 8.1 nM). Pretreatment with the V1 antagonist abolished these AVP-evoked responses. The data support the conclusion that the agonist binding occurs at a homogeneous population of V1-subtype receptors in the high-affinity (KD = approximately 1 nM) state and that these receptors are functionally coupled to phospholipase C.

Angiotensin Receptor Antagonists↗
PubMed1991

Effects of staurosporine on the pressor responses to alpha-adrenoceptor agonists in pithed rats: a comparison with nifedipine.

The effects of the calcium channel antagonist nifedipine and the protein kinase C (PKC) inhibitor, staurosporine were examined on the pressor actions of a full, cirazoline, and a partial, St587, alpha 1-adrenoceptor agonist as well as the alpha 2-adrenoceptor agonist B-HT 920 in the pithed rat preparation. Administration of nifedipine or staurosporine significantly reduced the diastolic blood pressure of pithed rats. Staurosporine displaced the dose-diastolic pressure response curves for B-HT 920 and St587 to the right in a dose-dependent manner. The ED50 value for the dose-response curves to B-HT 920 and St587 were found to be significantly increased after the administration of staurosporine. Staurosporine also caused a depression of the maximum response to B-HT 920 and St587. The presence of nifedipine resulted in an increase in the ED50 value of the dose-response curve to B-HT 920 and St587, and this was accompanied by significant reductions of the maximum response, whereas the administration of either staurosporine or nifedipine did not significantly affect the calculated ED50 value of the dose-response curve to cirazoline. In the presence of the calcium channel antagonist but not the PKC inhibitor the maximum response to cirazoline was significantly depressed. As judged from the slope function of the dose-response curves the nature of the inhibition produced by nifedipine compared to staurosporine also appeared to differ. Thus, with nifedipine as the antagonist, the slope function of the dose-response curve for alpha-agonists was significantly reduced. Moreover, in contrast to the actions of staurosporine, nifedipine reduced the maximum response to cirazoline in a dose-independent manner. This study supports the hypothesis that activation of alpha-adrenoceptors that have a substantial dependence on extracellular calcium for vasoconstriction are susceptible not only to the action of calcium channel antagonists but also to the actions of the PKC inhibitor staurosporine, thus suggesting that PKC may modulate directly/indirectly calcium channel activity in vascular smooth muscle.

Adrenergic alpha-Agonists↗
PubMed1991

Prevention of hypertension and vascular changes by captopril treatment.

Treatment of female spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats with captopril was carried out by the addition of the drug in the drinking water throughout pregnancy and lactation and after weaning. At 28 weeks of age, average systolic blood pressure of treated SHR was 113 +/- 3 mm Hg, which was below that of control SHR (188 +/- 3 mm Hg) and WKY rats (124 +/- 3 mm Hg). Body weight and heart rate of the SHR were not affected by the treatment. Tissue level of catecholamines was increased by captopril treatment in the superior cervical ganglia but remained unchanged in the plasma, heart, mesenteric arteries, and the adrenal glands of both SHR and WKY rats. Left ventricular weight, wall thickness, and internal diameter of the left ventricle in the SHR were reduced by the treatment. Morphometric measurements of the mesenteric arteries showed that vascular alterations present in the control SHR were prevented by the treatment. In the superior mesenteric artery and large mesenteric artery, smaller lumen size at maximal relaxation found in the control SHR was normalized to the level of the WKY rats. Hypertrophy of the medial wall in the superior mesenteric, large and small mesenteric arteries, and an increase in the number of smooth muscle cell layers in the large mesenteric artery of the SHR were prevented by the treatment. Perfusion study of the mesenteric vascular bed showed that reactivity of these vessels to norepinephrine was reduced, and sensitivity to norepinephrine (as determined by the effective dose that causes 50% of maximal response) was increased in the SHR by captopril treatment. Sensitivity of the tail artery in response to norepinephrine was not altered by the treatment. We conclude that long-term treatment with captopril of SHR before and after birth prevented the development of hypertension, structural and functional alterations of the mesenteric arteries, and cardiac hypertrophy.

Animals↗
PubMed1990

Alpha-adrenoceptor activation of polyphosphoinositide hydrolysis in the rat tail artery.

alpha-Adrenoceptor coupling to polyphosphoinositide (PI) hydrolysis was studied in the rat tail artery. Inositol phosphate (IP) accumulation was stimulated by the non-selective alpha-adrenoceptor agonist norepinephrine and the alpha 1-adrenoceptor agonist phenylephrine. This stimulation was relatively dependent on extracellular Ca2+ and enhanced markedly in the presence of LiCl. In addition, norepinephrine- and phenylephrine-stimulated IP accumulation was relatively sensitive to blockade by prazosin, compared to rauwolscine. The putative alpha 2-adrenoceptor agonist UK 14304 also stimulated PI breakdown in a concentration-dependent manner, although this stimulation did not reach equilibrium at up to 10 mM and was relatively sensitive to prazosin, compared to rauwolscine, over the lower agonist concentrations. NaF stimulated IP accumulation independently of alpha-adrenoceptor activation. PI breakdown by alpha-adrenoceptor agonists and NaF was attenuated by N-ethylmaleimide but not pertussis toxin treatment. In addition, dithiothreitol blocked NaF-stimulated, but not alpha-adrenoceptor-mediated. PI breakdown. These results suggest the coupling of alpha 1-adrenoceptor, via phospholipase C, to PI hydrolysis in the rat tail artery. This study also provides evidence for the involvement of one or more non-Gi-like G-protein(s) in the signal transduction process.

Animals↗
PubMed1990

Studies of the desensitization of atrial natriuretic factor and nitroglycerin in rat aortic rings.

1. Atrial natriuretic factor (ANF) relaxes vascular smooth muscle through activation of particulate guanylate cyclase and generation of cyclic GMP. 2. From other laboratories, there is some evidence from cultured vascular smooth muscle cell studies for homologous desensitization of ANF-induced cGMP production and down-regulation of ANF receptors. 3. This series of studies demonstrates that homologous desensitization of ANF-induced relaxation of rat aortic ring preparations also occurs. 4. Heterologous desensitization could not be demonstrated to the vasoactive peptides angiotensin II or vasopressin, nor to nitroglycerin which has previously been shown to exhibit heterologous desensitization with other nitrovasodilators and shares some common elements in the pathway to vascular smooth muscle relaxation with ANF.

Animals↗
PubMed1990

Effects of nifedipine, BAY K 8644, and pertussis toxin on pressor response to sarafotoxin-b in pithed rats.

The pressor actions of sarafotoxin-b (SRTX-b) were examined in pithed rats in the presence of the calcium channel antagonist nifedipine or the calcium channel activator BAY K 8644 intraarterially (i.a.) and also after pretreatment with pertussis toxin intravenously (i.v.). SRTX-b produced dose-dependent pressor effects in the pithed rat. The diastolic blood pressure (DBP) recorded in animals treated with the vehicle was 41 +/- 1 mm Hg; administration of BAY K 8644 0.1 or 0.3 mg/kg increased DBP pressure to 50 +/- 1 and 52 +/- 1 mm Hg, respectively, whereas nifedipine 0.1 or 0.3 mg/kg decreased DBP to 39 +/- 1 and 33 +/- 1 mm Hg, respectively. The actions of SRTX-b were significantly inhibited by nifedipine, whereas BAY K 8644 potentiated the pressor actions of SRTX-b. We observed that animals pretreated with pertussis toxin 25 or 50 micrograms/kg 3 days before we conducted the experiments had significantly lower DBP as compared with saline-treated animals. Treatment with pertussis toxin caused the DBP dose-response curve to SRTX-b to be displaced to the right. These results indicate that a nifedipine-sensitive (presumably extracellular) calcium pool is partly responsible for the pressor response induced by SRTX-b. They further suggest that in vascular smooth muscle, at least in some vascular beds, SRTX-b activates a pertussin toxin-sensitive G-protein that is coupled to a receptor-operated calcium or nonspecific cation channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Calcium antagonizes the magnesium-induced high affinity state of the hepatic vasopressin receptor for the agonist interaction.

1. The present study describes the role of Ca2+ in the regulation of the hepatic vasopressin V1 receptor. With low concentrations of Ca2+, there was a small increase in [3H]-arginine vasopressin [( 3H]-AVP) binding, but above 10 mM, Ca2+ decreased the binding of this agonist. In contrast, low concentrations of Mg2+ were associated with a dramatic concentration-dependent increase in [3H]-AVP binding, reaching a maximal effect of 650% above control at concentrations ranging between 1-5 mM. At higher concentrations of Mg2+, the stimulatory effect of this cation was less pronounced, falling to 210% of control at 100 mM Mg2+. Strikingly, Ca2(+)-inhibited the stimulatory effect of Mg2+ in a concentration-dependent fashion. 2. Saturation binding data revealed that Ca2+ (2 to 10 mM) per se promotes the high affinity conformation of the V1 receptor for the agonist binding with the KD decreased from a control value of 2.3 nM to 0.5 nM in the presence of 10 mM Ca2+. This effect was attenuated with an increase in Ca2+ above 10 mM. With an increase in Ca2+ to 20 mM, however, the Bmax for [3H]-AVP binding was decreased. Ca2+ also decreased the high affinity/high capacity state (KD 100 pM) of the receptor induced by 1 mM Mg2+ for agonist interaction. 3. [3H]-V1 antagonist binding was inhibited by both Ca2+ and Mg2+. The IC50 values (mean +/- s.e. mean) for Ca2+ and Mg2+ were 32 +/- 8 and 53 +/- 9 mM respectively. Maximal inhibition achieved at 100 mM was 29% for Ca2+ and 42% for Mg2+. Both cations decreased the affinity and increased the capacity of the V1 receptor for the antagonist. 4. The results suggest that the divalent metal ion binding site(s) modulated by Mg2 + is also accessible to Ca2 +. Although Ca2 + opposes the powerful stimulatory effects of Mg2 + on agonist binding, the effects of Ca2+ and Mg2 + on the B,,x of [3H]-AVP binding were different, suggesting that the divalent cations may bind to two different sites, thereby regulating the affinity and the capacity characteristics of the V1 receptor.

Animals↗
PubMed1990

Comparison between the vasoactive actions of endothelin and arginine vasopressin in pithed rats after pretreatment with BAY K 8644, nifedipine or pertussis toxin.

Both human endothelin 1 (ET1) and rat endothelin 3 (ET3) produced dose-dependent pressor effects in the pithed rat. The pressor actions of ET3 and arginine vasopressin (AVP) were compared with one another in pithed rats in the presence of the calcium channel activator BAY K 8644 or the calcium channel antagonist nifedipine i.a. and also after pretreatment with pertussis toxin i.v. The diastolic pressure recorded in animals treated with the vehicle was 41 +/- 1 mm Hg, and administration of BAY K 8644 increased the diastolic pressure to 53 +/- 3 mm Hg, whereas nifedipine caused a decrease in diastolic pressure to 33 +/- 2 mm Hg. AVP, ET1 and ET3 dose-dependently increased diastolic blood pressure, with AVP being the most potent and producing the greatest total increase in pressure. ET1 was more potent than ET3; however, the maximal increases produced by the endothelins were identical. The actions of ET3 but not AVP were potentiated in the presence of BAY K 8644. Furthermore, nifedipine significantly impaired responses induced by endothelin but not those produced by AVP. It was observed that animals treated with pertussis toxin 3 days before the conduction of the experiments had a significantly lower diastolic blood pressure as compared with saline-treated animals. Treatment with pertussis toxin caused the dose-diastolic pressure response curve to ET to be displaced to the right, whereas the dose-diastolic pressure response to AVP was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Comparative behavioral, neurochemical and pharmacological activities of dihydropyridine calcium channel activating drugs.

The behavioral (deficits in motor function in mice), neurochemical (affinity for mouse brain membrane dihydropyridine receptors, effects on neurotransmitter/metabolite levels in mice) and pharmacologic (effect on the contractile activity of guinea pig ileal longitudinal smooth muscle) properties of the calcium channel activators (+/-)-BAY K 8644, (+/-)-202-791 (and their corresponding channel activating and antagonist enantiomers) and CGP-28392 were investigated and compared. The calcium channel activating enantiomers (-)-S-BAY K 8644, (+)-S-202-791 and (+/-)-BAY K 8644, (+/-)-202-791 and CGP-28392 produced a dose-dependent impairment of rotarod ability and decreases in motor activity in mice with the following order of potency: (-)-S-BAY K 8644 greater than (+/-)-BAY K 8644 much greater than (+)-S-202-791 greater than (+/-)-202-791 = CGP-28392. The calcium channel antagonists (+)-R-BAY K 8644 and (-)-R-202-791 were behaviorally inactive but blocked the behavioral effects of (-)-S-BAY K 8644. The binding of dihydropyridine calcium channel activator and antagonist enantiomers to mouse brain membranes was described by both one and two site models. (-)-S-BAY K 8644, (+/-)-BAY K 8644, (+)-S-202-791 and CGP-28392 produced contractions in partially depolarized (15 mM K+) strips of guinea pig ileal longitudinal smooth muscle which differed in the degree of maximum contraction obtained. (+)-R-BAY K 8644 and (-)-R-202-791 inhibited potassium-induced contractions (80 mM K+) in guinea pig ileal longitudinal smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Benextramine and nifedipine distinguish between sub-classes of alpha 1-adrenoceptors.

The effects of benextramine and nifedipine were examined on the dose-diastolic pressure response to methoxamine in pithed normotensive rats. Benextramine (3, 6 and 12 mg/Kg) displaced the dose-response curve to methoxamine to the right. Maximum response was reduced after the administration of 12 mg/Kg benextramine. Nifedipine (0.1 and 0.3 mg/Kg) also caused the dose-response curve to methoxamine to be displaced to the right with reduction in maximum response. Nifedipine effects were additive with an increase in the EC50 values as well as reduction in the maximum response after pretreatment with benextramine (3 and 6 mg/Kg). However, at the highest dose of benextramine the effects of nifedipine were diminished and no longer apparent. It is concluded that benextramine may have alkylated a nifedipine sensitive site on the alpha 1-adrenoceptors.

Animals↗
PubMed1989

Lipids as endogenous Na,K-ATPase inhibitors in plasma of healthy individuals and in dialysis dependent patients.

We assayed plasma Na,K-ATPase inhibitory activity due to total lipids and lipid fractions. The effect of dialysis on the Na,K-ATPase inhibitory activity was also studied. Plasma lipid extracts from 11 healthy volunteers and 9 dialysis-dependent patients (pre and post dialysis) were separated into neutral lipids and phospholipids. Further fractionation was by thin layer chromatography. These lipid fractions were analyzed for Na,K-ATPase inhibitory activity by displacement of [3H]-ouabain from hog brain Na,K-ATPase. Total inhibitory activity was significantly increased (p less than 0.001) in the post-dialysis plasma compared to pre-dialysis plasma of the same patient group and to controls (482, 85 and 78 nmol/L respectively; means of the groups in digoxin equivalents). The major inhibitory activity was associated with non-esterified fatty acids with modest contributions from four other lipid fractions. Our results show that endogenous lipids are major plasma Na,K-ATPase inhibitors in vitro under these assay conditions.

Adult↗
PubMed1988

Alpha adrenoceptor sites in vascular smooth muscle. Differentiation by selective antagonist binding.

The properties of alpha adrenoceptors in rat-tail artery membranes were studied using tritiated ligands that are selective for the alpha 1 and alpha 2 subtypes. High-affinity saturable binding was obtained for the alpha 1 antagonist prazosin yielding a Bmax of 144 +/- 31.6 fmol/mg protein (mean +/- SEM, N = 3) and a Kd of 0.17 +/- 0.04 nM, and also for the alpha 2 antagonist rauwolscine which yielded a Bmax of 141.3 +/- 19.3 fmol/mg protein and a Kd of 1.57 +/- 0.32 nM. The [3H]prazosin-labelled sites displayed a pharmacological profile characteristic of an alpha 1 adrenoceptor, whereas the [3H]rauwolscine-labelled sites exhibited the expected alpha 2 adrenoceptor profile. Agonist affinity for [3H]rauwolscine sites was reduced by Gpp(NH)p and Na+, and the effects appeared synergistic for adrenaline, but non-interactive for UK-14304. Agonist interaction with [3H]prazosin sites in the rat-tail artery was also regulated by Gpp(NH)p and Na+, although clearly in a qualitatively and quantitatively different manner from the [3H]rauwolscine sites. These results suggest that distinct binding sites for [3H]prazosin and [3H]rauwolscine could be differentiated with antagonist ligands. These distinct antagonist recognition sites demonstrate the pharmacological profile expected for alpha 1 and alpha 2 adrenoceptors, and the quantitatively differing abilities of Na+ and Gpp(NH)p to regulate agonist interactions with these sites are suggestive, but do not necessarily prove, that different G proteins may be involved in this regulation.

Animals↗
PubMed1988

Inhibition of field stimulation-evoked relaxations in rat oesophageal smooth muscle by the calcium antagonist PN 200-110.

1. The inhibitory effects of the 1,4-dihydropyridine calcium channel antagonist, PN 200-110 (isradipine), on field stimulation-evoked tetrodotoxin (TTX)-sensitive and -insensitive relaxations were studied in rat oesophageal smooth muscle of the tunica muscularis mucosae. 2. The TTX-insensitive relaxation was inhibited by PN 200-110 in a stereoselective manner with the (+)-(S)-isomer displaying a 1000 fold greater inhibitory potency than the (--)-(R) isomer. A similar potency was noted for inhibition of high K+ -evoked contractions. 3. TTX-sensitive relaxations evoked by field stimulation and contractions elicited by the muscarinic cholinoceptor agonist, cis-2-methyl-4-dimethylamino-methyl-1,3-dioxolane methiodide (cisdioxolane) were considerably less sensitive to inhibition by PN 200-110, although, again, stereoselectivity for PN 200-110 was apparent. 4. Pretreatment with (+)-(S)-PN 200-110 resulted in a non-competitive displacement of the Ca2+ concentration-response curves obtained in the presence of either isotonic 50 mM KCl or cisdioxolane. The effect of K+ was 10 fold more sensitive than that of cis-dioxolane. 5. The potency rank orders for inhibition of TTX-insensitive field stimulation-evoked relaxations and K+ -mediated contractions in a series of calcium channel antagonists were closely correlated; (+)-(S)-PN 200-110 showing highest potency followed by nifedipine, verapamil, diltiazem, (--)-(R)-PN 200-110. 6. It is concluded that TTX-insensitive relaxations are dependent upon an influx of extracellular Ca2+ through potential-operated calcium channels.

Animals↗
PubMed1988

Similarity of relaxations evoked by BRL 34915, pinacidil and field-stimulation in rat oesophageal tunica muscularis mucosae.

1. In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 and pinacidil, raised the threshold for concentration-dependent K+ contractions, suppressed contractions evoked by field stimulation of the TMM in the presence of tetrodotoxin (TTX) and tetraethylammonium (TEA), and relaxed tonic contractions resulting from muscarinic cholinoceptor stimulation. 2. BRL 34915 and both (+)- and (--)-pinacidil increased 86Rb efflux from tracer-loaded tissues; nifedipine abolished this effect. 3. Relaxations produced by potassium channel openers were inhibited by a temperature drop from 37 degrees C to 26.5 degrees C, an increase in extracellular K+ concentration to 64 mM, and treatment with the calcium channel antagonist, nifedipine. The same treatments also blocked field stimulation-evoked TTX-insensitive relaxations. 4. It is concluded that field stimulation of rat oesophageal smooth muscle in the presence of cholinoceptor-induced tone results in an increase in K+ permeability that is directly or indirectly coupled to Ca2+ influx through potential-operated channels.

Animals↗
PubMed1988

Hepatic vasopressin receptor: differential effects of divalent cations, guanine nucleotides, and N-ethylmaleimide on agonist and antagonist interactions with the V1 subtype receptor.

Previously, we reported that magnesium (Mg2+) enhanced the binding affinity of arginine vasopressin [( 3H]AVP) to a single class of sites in rat liver microsomes. In the present study we have examined the effects of divalent cations and guanine nucleotides on the binding characteristics of both the nonselective agonist and the V1 receptor-selective antagonist, d(CH2)5Tyr(Me)-[3H]AVP, to microsomal and plasma membrane fractions of rat liver. At a subsaturating concentration (100 pM) of [3H]AVP, divalent cations increased specific binding in a concentration-dependent manner with the following rank order of potency: Co2+ greater than Mn2+ greater than Ni2+ greater than Mg2+ greater than Ca2+ = control. The maximal effect for Mg2+ was evident at 1 mM, a physiologically relevant concentration. In contrast, binding of the V1 receptor antagonist (at a subsaturating concentration of 10 pM) was inhibited by divalent cations, the rank order of potency being Mn2+ greater than Co2+ greater than Ca2+ greater than Mg2+ greater than Ni2+. The inhibitory effects of divalent cations were of lesser magnitude (up to 60%) compared to the stimulation of agonist binding (up to 700%). Mg2+ enhanced the affinity of [3H]AVP (Kd was decreased from approximately 2 nM to 133 pM), while the affinity of the [3H]V1 antagonist was decreased (Kd was increased from 10 to 95 pM). Scatchard analysis of saturation data (Mg2+ present) revealed similar maximum binding values for the binding of radiolabeled agonist and antagonist, indicating that AVP receptors in rat liver are mostly of the V1 subtype. Competition experiments between V1/V2-specific AVP analogs with either the radiolabeled agonist or antagonist also indicated the presence of predominantly V1 receptor sites in rat liver microsomes. The properties of plasma membrane receptor sites were similar to those of the microsomal sites, except that the density of receptors was higher in the former. In both equilibrium and competitive inhibition experiments GTPase-resistant analogs of guanine nucleotides, GTP gamma S and GDP beta S, decreased the affinity of the agonist for the receptor, but not that of the antagonist. Treatment of membranes with 0.2 mM N-ethylmaleimide (NEM) reduced the maximum binding of [3H]AVP and abolished the GTP gamma S-evoked decrease in agonist-binding affinity. In contrast, antagonist binding was unaffected by NEM. NEM pretreatment failed to influence the divalent cation-dependent increase in agonist-binding affinity. The results provide direct evidence for the existence of a high and a low affinity state of the hepatic V1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety.

Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl greater than 3-trifluoromethyl(nitro)phenyl greater than 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5-dicarboxylat es (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the l-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3, 5-dicarboxylates (9).

Animals↗