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Graphical Abstract:

Three 1,5-diarylpyrazoles were synthesized and pre-formulated with polyvinylpyrrolidone to enhance the antidiabetic activity, evaluated on in vivo non-insulin dependent diabetes mellitus model. Additionally, an in vivo subacute test was conducted to quantify antidiabetic, lipidic profile and antidyslipidemic activity. Spectroscopic techniques together with microscopy confirmed drug-carrier interaction. Notably, the antidiabetic activity of a dehalogenated pyrazole was twofold enhanced with the pre-formulation. This treatment also displayed antihyperglycemic activity without producing hypoglycemia, while a sub-acute study demonstrated that the solid dispersion has benefits in improving dyslipidemia, specifically reducing triacylglycerols, an effect scarcely observed with the reference drug metformin. Therefore, solid dispersion pre-formulation offers a simple but effective approach for enhancing the peripheral action of cannabinoid receptor 1 antagonist, thus minimizing undesired effects while enhancing antidiabetic and related metabolic properties.

Background: Hypertension is a complex and multifactorial disorder that is an important cause of morbidity and mortality in all around the world; and the rationalized structural modification of drugs represents an important strategy for to develop new antihypertensive drugs. Objective: To determine the vasorelaxant effect of 4H-pyranes and 2-pyridones derivatives designed from nifedipine and milrinone as pharmacophoric scaffolds. Methods: The vasorelaxant effect of all designed and synthesized compounds were carried out on the contraction induced by noradrenaline 0.1 μM in isolated rat aorta rings. Results: Compounds 4a—j, 6a-c and 8a-c showed a concentration– dependent and endothelium-independent relaxation on contraction induced by noradrenaline in isolated rat aorta rings. Compounds 6a, 8a, 8b, and 8c were the most potent compounds of entire series evaluated; however, were less potent than nifedipine and carbachol used as positive controls. Conclusions: Some compounds were designed and synthesized with significant vasorelaxant effect which can be used for the development of new antihypertensive drugs.

Studies in mature adults suggest that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) provides a simple way to identify apparently healthy individuals who are insulin resistant (IR) and at increased cardiometabolic risk. This study extends these observations by examining the clinical utility of the TG/HDL-C ratio and the metabolic syndrome (MetS) in 2,244 healthy college students (17–24 years old) of Mexican Mestizo ancestry. The TG/HDL-C ratio separating the 25% with the highest value was used to identify IR and increased cardiometabolic risk. Cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively, and approximately one third were identified as being IR. The MetS identified fewer individuals as being IR, but their risk profile was accentuated. In conclusion, both a higher TG/HDL-C ratio and a diagnosis of the MetS identify young IR individuals with an increased cardiometabolic risk profile. The TG/HDL-C ratio identified a somewhat greater number of “high risk” subjects, whereas the MetS found a group whose risk profile was somewhat magnified. These findings suggest that the TG/HDL-C ratio may serve as a simple and clinically useful approach to identify apparently healthy, young individuals who are IR and at increased cardiometabolic risk.

Calcium channel blockers are widely used in therapy for hypertension and angina pectoris, and among these blockers some 1,4-dihydropyridines (e.g. amlodipine, nitrendipine and nifedipine) have had widespread clinical use. In this work we investigated the vascular effects of four bis-1,4-dihydropyridines (bis-DHPs: 01-04), structurally related to nifedipine, in which a second 1,4-dihydropyridinic moiety was incorporated in the corresponding arylic moiety in para and meta position. Of these four bis-DHPs, the meta regioisomers (bis-DHP-03 and bis-DHP-04; 0.01-3.16 mg kg-1) and nifedipine induced a greater decrease on diastolic and systolic blood pressure than the para isomers (bis-DHP-01 and bis- DHP-02), as shown in two experimental models: normotensive and spontaneously hypertensive rats. Complementarily, bis-DHPs action was examined in intact and endothelium-denuded rat aorta, depolarized by KCl [80 mM] in one group and stimulated by noradrenaline (1x10-7 M) in another and the corresponding IC50 values were obtained (1.5x10-6-2.4x10- 7M). Later, the relaxing action of bis-DHP-03,04 and nifedipine on the contraction evoked by Ca2 in K-depolarized rat aorta was analyzed and the corresponding EC50 values for the meta isomers and nifedipine were obtained. The results showed a concentration dependent vasodilating activity in both KCl precontracted and noradrenaline stimulated aorta rings. The apparent order of potency with and without endothelium in both experimental models was nifedipine>bis-DHP- 04>bis-DHP-03. The cumulative concentration-effect curves for Ca2 in the presence of the bis-DHPs tested show the same potency order. Unlike nifedipine, the tested compounds are not photosensitive, which makes them more attractive in therapy for hypertension related diseases.

The effects of chloroethylclonidine on α1‐adrenoceptor‐mediated contraction in endothelium‐denuded caudal arteries and aorta from normotensive Wistar and Wistar Kyoto (WKY), and from spontaneously hypertensive (SHR) rats were evaluated.Chloroethylclonidine elicited concentration‐dependent contractions. Maximal contraction was similar in caudal arteries among strains (∼40% of noradrenaline effect). However, chloroethylclonidine elicited a higher contraction in aorta from SHR than from normotensive rats. In Wistar aorta chloroethylclonidine produced the smallest contractile response.In SHR aorta, BMY 7378 and 5‐methylurapidil blocked chloroethylclonidine‐elicited contraction, while (+)‐cyclazocine did not inhibit it; while in caudal arteries, 5‐methylurapidil blocked chloroethylclonidine action; the other antagonists had no effect.In chloroethylclonidine‐treated aorta noradrenaline elicited biphasic contraction‐response curves, indicating a high affinity (pD2, 8.5–7.5) chloroethylclonidine‐sensitive component and a low affinity (pD2, 6.3–5.2) chloroethylclonidine‐insensitive component. The high affinity component was blocked by chloroethylclonidine; while in caudal arteries noradrenaline elicited monophasic contraction‐response curves with pD2values (6.5–5.7) similar to the low affinity component in aorta.Chloroethylclonidine inhibition of noradrenaline response was greater in aorta than in caudal arteries. Chloroethylclonidine increased the EC50values of noradrenaline ∼1000 fold in aorta and ∼10 fold in caudal arteries.In SHR aorta BMY 7378 protected α1D‐adrenoceptors and in caudal arteries 5‐methylurapidil protected α1A‐adrenoceptors from chloroethylclonidine alkylation, allowing noradrenaline to elicit contraction.These results show marked strain‐dependent differences in the ability of chloroethylclonidine to contract aorta; moreover, chloroethylclonidine stimulates α1D‐adrenoceptors in aorta and α1A‐adrenoceptors in caudal arteries. The higher contraction observed in aorta from SHR and WKY suggests an augmented number of α1D‐adrenoceptors in these strains.

The subtype selectivity of the α 1 - adrenoceptor antagonist, tasulsion, was tested using hepatocytes and liver membranes from guinea pigs and rabbits (expressing α 1 - adrenoceptors with α 1 A pharmacology) and rats ( α 1 B - adrenoceptors ). Tamsulosin blocked the α 1 - adrenergic activation of phosphorylase with higher affinity in epatocytes from guinea pigs and rabbits than in those from rats. [ 3 H]Tamsulosin binding to liver membranes was rapid, reversible and saturable. The K d values obtained also indicated higher affinity for α 1 A - adrenoceptors (70 and 140 pM, forliver membranes obtained from guinea pigs and rabbits, respectively) than for those of the α 1 B - subtype (510 pM). Chloroethylclonidine potently and completly inactivated [ 3 H]tamsulosin binding sites in membranes from rabbit and rat livers, but not those in guinea pig liver membranes. Binding competition and inactivation experiments were performed to further characterize the receptor subtypes present in the livers of these animals. In summary, tamsulosin is a very potent α 1 - adrenoceptor antagonist that has higher affinity for α 1 A - adrenoceptors than for those of the α 1 B - subtype .

The effect of several α1adrenoceptor antagonists on the α1-adrenoceptor-mediated stimulation of phosphatidylinositol labeling was studied comparatively in rat hepatocytes and rabbit aorta. It was observed that 5-methyl urapidil and WB 4101 were much more potent in rabbit aorta than in hepatocytes. The orders of potency were prazosin ≫ 5-methyl urapidil ≥ WB 4101 in liver cells and WB 4101 ≥ 5 methyl urapidil = prazosin in aorta. Treatment with chlorethylclonidine inhibited 70–80% of the stimulation of labeling induced by epinephrine in rat liver, but only 30–40% of that in aorta. Our data suggest the existence of two pharmacologically distinct receptors in these tissues i.e., α1A-adrenoceptors in aorta and α1Bin liver cells.

In catfish hepatocytes (Ictalurus punctatus) α₁-adrenergic activation by epinephrine or norepinephrine increased cytosol Ca²⁺ concentration. This effect was inhibited by α₁-adrenergic antagonists with the potency order WB4101 > benoxathian  5-methylurapidil > phentolamine > (+)niguldipine. Pretreatment with the irreversible antagonist, chloroethylclonidine, reduced the α₁-adrenergic effect. α₁-Adrenergic stimulation also increased the resynthesis of phosphatidylinositol in whole cells. In liver membranes, a relatively small (33 fmol/mg of protein) number of sites with high affinity (K_d 100 pM) for the radioligand [¹²⁵I]HEAT was detected. Binding competition experiments showed the following orders of potency: (1) for agonists, oxymetazoline > epinephrine  norepinephrine > methoxamine; (2) for antagonists, prazosin > WB4101 > benoxathian  5-methylurapidil > phentolamine > (+)niguldipine. Membrane pretreatment with chloroethylclonidine markedly reduced [¹²⁵I]HEAT binding. Good correlation was observed between the radioligand binding studies and the functional data with isolated cells. The present data suggest that the α₁-adrenoceptor present in catfish liver cells belongs to the α_1B subtype. Copyright 1995, 1999 Academic Press

This study was designed to determine if α1-adrenoceptors are involved in the vascular responses to 5-HT1Areceptor agonists. Buspirone (3.1 × 10−7–3.1 × 10−5M) and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT; 3.1 × 10−6–10−4M) el elicited contractions of rabbit aorta rings which were blocked by prazosin (10−9–5.6 × 10−9M), but which were unaffected by reserpine pretreatment (1 mg/kg i.p.). 5-Methylurapidil (10−7and 10−6M) blocked contractions elicited by 8-OH-DPAT and by buspirone, whereas chloroethylclonidine (10−5and 10−4M) inhibited only the effect of buspirone. In addition, these 5-HT1Areceptor agonists relaxed arteries precontracted with α-adrenoceptor agonists in a similar range of concentrations in which they elicited contraction. Moreover, 8-OH-DPAT and buspirone protected the α-adrenoceptors from the irreversible blockade provoked by phenoxybenzamine (10−7M), as judged by the norepinephrine contraction and stimulated phosphatidylinositol labeling. According to these results the contractile and relaxant effects elicited by 5-HT1Areceptor agonists are a consequence of a direct interaction with α1-adrenoceptors. The contraction elicited by 8-OH-DPAT may be mediated by α1A-adrenoceptors, whereas both α1A- and α1B-adrenoceptors may mediate the effect of buspirone in rabbit aorta.

The role of α1D‐adrenoceptors in the vasculature of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY), of different ages was assessed in pithed rats by the use of the selective α1D‐adrenoceptor antagonist BMY 7378 (8‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]‐ethyl]‐8‐azaspiro [4.5]decane‐7,9‐dione dihydrochloride). BMY 7378 displaced the pressor effect of phenylephrine in young pre‐hypertensive pithed SHR rats, but produced no effect in young WKY rats (dose ratio of 3.4 and 1.6, respectively), while in adult rats BMY 7378 produced a greater shift in the phenylephrine response curve than in younger animals (dose ratio of 3.2 and 6.2 in WKY and SHR, respectively). The presence of α1D‐adrenoceptors in the vasculature of pre‐hypertensive rats, suggests its role in the pathogenesis/maintenance of increased blood pressure.

The effect of norepinephrine and epinephrine on the activity of low KmGTPase was studied in striata from young and old rats. Results showed that the amines stimulated the low KmGTPase activity of both young and old animals in a concentration-dependent manner. There was no differential effect of the amines as a function of age, but the stimulated low KmGTPase activity was significantly lower in the aged tissue.

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