Monika Kubacka

The hypotensive activity and alpha1-adrenoceptor antagonistic properties of some aroxyalkyl derivatives of 2-methoxyphenylpiperazine.

In the search for new hypotesive agents a series of aroxyalkyl derivatives of 2-methoxyphenylpiperazine was obtained. The aim of the present study was to examine their hypotensive properties and to evaluate their mechanism of action. In the study their hypotensive activity after i.v. and p.o. administration, influence on the pressor responses to adrenaline, noradrenaline and methoxamine, direct spasmolytic and vasorelaxant effects were assessed. In the next step two compounds which were the most active and selective for α(1)-adrenoceptors were evaluated for their α(1)-adrenoreceptor subtypes selectivity in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested aroxyalkyl derivatives of 2-methoxyphenylpiperazine is mainly a result of their α(1)- or α(1)/α(2)-adrenoceptor blocking properties. The two most active compounds showed to be the competitive antagonists of α(1)-adrenoceptors with stronger activity at α(1D)-, α(1A)- and α(1L)- and weaker at α(1B)-subtype.

Antinociceptive, anti-inflammatory and smooth muscle relaxant activities of the pyrrolo[3,4-d]pyridazinone derivatives: Possible mechanisms of action.

The aim of this study was to evaluate the analgesic as well as anti-inflammatory activities of the new pyrrolo[3,4-d]pyridazinone derivatives. Moreover, the present study attempted to assess some of the mechanisms involved in the pharmacological activity of these compounds. In the previous studies it was shown that these compounds were highly active in the phenylbenzoquinone-induced writhing syndrome test and had much lower activity in the hot plate, which indicates that mainly peripheral mechanisms of analgesia are involved in their effects. In these extended studies the analgesic activity of two tested compounds (4c, 4f) was confirmed in some animal models of pain. The studied compounds showed a significant and dose-related antinociceptive effect in the models of pain induced by formalin, capsaicin and glutamic acid. Both compounds decreased the edema formation and one of them (4c) attenuated mechanical hyperalgesia in carrageenan-induced paw inflammation in rats. Furthermore, both compounds inhibited cell migration, plasma exudation and nociceptive reaction in zymosan A-induced mouse peritonitis. In the subsequent studies, including experiments on isolated organs (ileum, trachea, aorta), radioligand assays and biochemical tests, it was demonstrated that analgesic and anti-inflammatory effects of the investigated structures are largely due to their competitive antagonism for histamine H1 receptor. The influence on the level of cAMP in inflammatory cells (shown in RAW 264.7 macrophages) and subsequent inhibition of cytokine (TNFα, IL-1β) release can also be one of the important mechanisms of their action. Moreover some additional mechanisms may also be involved in the eventual analgesic effect of tested pyrrolo[3,4-d]pyridazinone derivatives.

Antiarrhythmic properties of some 1,4-disubstituted piperazine derivatives with α1-adrenoceptor affinities

A series of 1,4-disubstituted piperazine derivatives with α1-adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity in vitro and in vivo. Most of them displayed strong antiarrhythmic activity in the adrenaline induced model of arrhythmia and in the rat coronary artery ligation-reperfusion model. Their antiarrhythmic effect is mainly related to α1-adrenolytic properties. Among them one compound showed characteristics similar to quinidine in different arrhythmia models as well as electrocardiogram (ECG) studies which suggests that it possesses not only α1-adrenoceptor blocking properties but also affinity for cardiac Na(+) and K(+) channels, similar to class IA antiarrhythmic agents. Two other compounds revealed some antioxidant effects. Another compound (MH-79) is particularly promising since it displayed a strong antiarrhythmic effect without the influence on ECG record.

Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action.

Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3, (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride), a partial 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A receptor activation is crucial for the antidepressant-like activity of compound 3. The rest of the compounds (except compounds 1 and 9) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies.

The possible mechanism of hypotensive activity of some pyrrolidin-2-one derivatives with antagonist properties at alpha1-adrenoceptors

In the search for new hypotensive agents a series of pyrrolidin-2-one derivatives was obtained with α-adrenoceptor blocking properties. The aim of the present study was to examine the possible involvement of other mechanisms in the observed hypotensive properties. In the present study the affinities for β₁-adrenoreceptors, vasorelaxant effect and the involvement in NO pathway of pyrrolidin-2-one derivatives were assessed. In the next step compounds were also evaluated for their α₁-adrenoreceptor subtypes in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested pyrrolidin-2-one derivatives is a result of their α-adrenoceptor blocking properties and the compounds have stronger antagonist potency for the α(1D)- than for α(1B)-subtype. Among investigated compounds EP-46 is the most potent and selective antagonist for the α(1D)- and α(1A)- than for α(1B)-subtype. Compound EP-43 can enhance NO production additionally.

Anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine is due to their 5-HT2A and α2-adrenoceptor antagonistic properties. A comparison with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239

Abstract Serotonin (5‐HT) and adrenaline acting at platelet 5‐HT2A‐serotoninergic and &agr;2‐adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5‐HT2A, &agr;2A–, and &agr;2B‐adrenoceptors as well as an anti‐aggregation effect of aroxyalkyl derivatives of 2‐methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2‐[2‐[4‐(o‐methoxyphenyl)‐piperazin‐1‐yl]‐ethyl]‐4,4‐dimethyl‐1,3‐(2H,4H)‐isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5‐HT2A and &agr;2‐adrenoceptors, with around 2–7 times stronger antagonistic effect at &agr;2B subtype than &agr;2A subtype. Further, studied compounds inhibited 5‐HT2A‐mediated contraction in isolated rat aortic rings and 5‐HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH‐77 (1‐[(2,3‐dimethylphenoxy)propyl]‐4‐(2‐methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5‐HT/adrenaline‐, amplified ADP‐ or collagen‐ induced platelet aggregation. Simultaneous, moderate blockade of 5‐HT2A serotonin and &agr;2‐adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy.

The Nitric Oxide/Soluble Cyclic Guanylase/Cyclic Guanosine Monophosphate Pathway Is Involved in the Cardiovascular Effects of a Novel α1- and β-Adrenoceptor Antagonist

The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.

Involvement of the NO/sGC/cGMP/K+ channels pathway in vascular relaxation evoked by two non-quinazoline α1-adrenoceptor antagonists

The aim of this study was to explore the α1-adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α1-adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1u202fμM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K+ efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, Nω-Nitro-l-arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α1-adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K+ channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α1-antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α1-adrenoceptors antagonists MH-76 and MH-79 involve not only α1-adrenoceptor blocking activity but also the activation of the endothelial NO-cGMP signalling pathway and the subsequent opening of K+ channels. Our studies show that such double mechanism of action is superior to pure α1-adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases.

Contents Vol. 94, 2014

C. Antoniou, Athens J. Ahrens, Hannover L.Z. Benet, San Francisco, Calif. M.L. Billingsley, Hershey, Pa. A. Breckenridge, London K.K. Burkhart, Silver Spring, Md. G. Coruzzi, Parma S. Dhein, Leipzig T.L. Goodfriend, Madison, Wisc. L.S. Harris, Richmond, Va. M. Hirafuji, Ishikari-Tobetsu M.D. Hollenberg, Calgary, Alta. M. Inui, Yamaguchi K. Ishii, Yamagata C. Joukhadar, Boston, Mass. Y. Kamisaki, Osaka N. Kaplowitz, Los Angeles, Calif. A. Kawabata, Osaka A. Levitzki, Jerusalem B.R. Lucchesi, Ann Arbor, Mich. W.E. Müller, Frankfurt am Main N.H. Neff , Columbus, Ohio J.P. O’Callaghan, Morgantown, W.Va. K. Pennypacker, Tampa, Fla. S. Saha, Kansas City, Mo. C. Scarpignato, Nantes C.D. Smith, Charlestown, S.C. E. Taira, Iwate C. Zeng, Chongqing City International Journal of Experimental and Clinical Pharmacology