1,721,122 research outputs found
1,4-DHP scaffold: calcium channel ligand based approach from cardiovascular to neuroprotective activity.
No full textAfter the pioneer studies of Fleckenstein and co-workers L-Type calcium channels (LTCC) blockers have attract large interest due to their effectiveness in treating several cardiovascular diseases (1). The 1,4-DHPs are known to be selective for smooth muscle than heart muscle. Nifedipine, the prototype of 1,4-DHP has been largely modified in several position in order to increase its selectivity towards the vascular smooth muscle. In the 1990s different Nifedipine derivatives have been shown to block different types of calcium channels. For these results, new therapeutic indications have been disclosed for the 1,4-DHP scaffold. Among the four classes of LTCC only CaV1.2 and CaV1.3 are pharmacologically targets, since no clinical applications have been proposed for CaV1.1 and CaV1.4 channels. Both CaV1.2 and CaV1.3 channels are expressed in the cardiovascular system where they exert different functions.
CaV1.2 channels control vascular tone and cardiac inotropy whereas CaV1.3 channels have a key role in the atrioventricular conduction system.
In the central nervous system (CNS), CaV1.2 channels are involved in depressant-like and Parkinson diseases. Nifedipine cause a variety of brain effect such as amelioration of age-related working memory deficits, anxiolytic and antidepressant-like actions and anticonvulsivant effects. In addition, it has to be considered the problem related to its therapeutic use for CNS diseases as the selectivity between central and peripheral LTCC.
Recently we describe the design, the synteshis and the structure activity relationship (SAR) of a small library of 1,4-DHPs with a imidazo[2,1-b]thiazole system variously replaced in C4. The chemical changes made, along with the profile of activity shown on isolated cardiac tissues made it possible to correlate the selectivity and potency in cardiac parameters with singular substituents in etherocyclic sistem. Using a ligand based approach and taking into account the inotropic or chronotropic selectivity of compounds, we design new compounds with the aime to improve seletivity. Based on these consideration, the development of selective modulators would make CaV1.3 channels suitable target to treat Parkinson disease, depression and drug abuse.
Since most of these SARs are common to all 1,4-DHPs we can conclude that the 1,4-DHP binding site of CaV1.2 and CaV1.3 channels are very similar and the identification of potent and selective compounds will be a hard task.
(1) Ioan, P.; Carosati, E.; Micucci, M.; Cruciani, G.; Broccatelli, F.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr. Med. Chem. 2011, 18, 4901-4922.
(2) Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.; Ugenti, M. P.; Andreani, A.; Di Toro, R.; Bedini, A.; Spampinato, S.; Marinelli, L.; Novellino, E.; Chiarini, A. J. Med. Chem. 2008, 51, 1592-1600
Xanthone 1,4-dihydropyridine derivatives with a potent selective bradycardic effect
No full textA series of xanthone 1,4-dihydropyridine derivates were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonistic properties. The tested compounds are weak calcium antagonists but exert potent selective bradycardic effects
Determination and Quantification of Pyrrolizidine Alkaloids in Natural Food Supplements by Quechers LC-MS/MS
No full textFluorenone and benzophenone 1,4-dihydropyridine derivatives with cardiodepressant activity
No full textA series of fluorenone and benzophenone 1,4-dihydropyridine derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties
Xanthone analogues of milrinone
No full textThe xanthone analogues of milrinone have been prepared. The new compounds do not retain the inotropic activity of the parent compound. Copyright © 1992 Journal of Heterocyclic Chemistr
Fig. 5 in Antihypertensive phytocomplexes of proven efficacy and well-established use: Mode of action and individual characterization of the active constituents
No full textFig. 5. Isolated components of Elettaria cardamomum (L.) Maton extract characterized for antihypertensive activity.Published as part of Micucci, M., Bolchi, C., Budriesi, R., Cevenini, M., Maroni, L., Capozza, S., Chiarini, A., Pallavicini, M. & Angeletti, A., 2020, Antihypertensive phytocomplexes of proven efficacy and well-established use: Mode of action and individual characterization of the active constituents, pp. 1-19 in Phytochemistry (112222) 170 on page 6, DOI: 10.1016/j.phytochem.2019.112222, http://zenodo.org/record/829299
Negative inotropic and chronotropic activity of calcium channel ligands possessing a xanthone 1,4-dihydropyridine backbone
No full textA series of xanthone 1,4-dihydropyridine derivatives were prepared. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist properties
Search for α1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an α(1D)-adrenoceptor antagonist
No full textTwo novel quinazolines (2 and 3) related to both prazosin and its open analogue 1 were synthesized, and their biological profile at α1- adrenoceptor subtypes was assessed by functional assays in rat isolated tissues, namely prostatic vas deferens (α(1A)), spleen (α(1B)) and aorta (α(1D)). Furthermore, the binding profile of 3 was assessed at native α2 and D2 receptors, and cloned human 5-HT(1A) receptors, in comparison to prazosin, (+)-cyclazosin, 1 and BMY 7383. It turned out that the cystamine- bearing quinazoline 3 (cystazosin) has a reversed affinity profile relative to (+)-cyclazosin owing to a higher affinity for α(1D)-adrenoceptors and a significantly lower affinity for the α(1A) and α(1B) subtypes. Furthermore, in comparison to BMY 7378, cystazosin (3) displays a much better specificity profile since it has lower affinity for D2 and 5-HT(1A) receptors
Molecular properties of the histamine H2-receptor. Covalent inhibition by tetraamine disulfides
No full textA series of tetraamine disulfides related to benextramine (an alpha-adrenoreceptor and H2-receptor antagonist) in which the distance between the inner and the outer nitrogens were changed from five to nine methylenes has been studied. Both effects of the displacement of the disulfide bridge by two methylenes and those of the progressive removal of two of the four nitrogens on the pharmacological profile have been assessed. Peak potency appeared to be associated with eight methylenes between the inner and the outer nitrogens and to four cationic charges as in the most active analogue 4 which was also investigated to assess its receptor specificity towards histamine H1 and muscarinic M2 and M3 receptors. The finding that the carbon analogue 11 (two methylenes for the disulfide bridge) was devoid of activity is consistent with the hypothesis that histamine H2-receptor inhibition is the result of a covalent bond formation by a way of a disulfide-thiol interchange reaction between the disulfide moiety of tetraamine disulfides and a receptor thiol group. However, the possibility that tetraamine disulfides may not act at the H2-receptor but beyond the receptor cannot be excluded
- …
