P-Adrenoreceptor antagonist

The production of reactive oxygen species (ROS) is associated with cytotoxicity. In the CNS, microglia are an important source of these species. In neonatal hamster microglia stimulated with phorbol myristate acetate, a PKC activator, isoproterenol reduces the production of superoxide anion and this decrease was blocked by a P-adrenoreceptors antagonist (Colton and Chernyshev, 1996). 

Tab. 4.17 Structural descriptors, physicochemical properties, and Caco-2 cell monolayer permeability coefficients of the P-adrenoreceptor antagonists (see Tab. 4.16). (Reprinted from Tab. 2 of ref. 54, with permission from the American Chemical Society)...

No adverse interactions have been reported in patients treated with lithium and P-adrenoreceptor antagonists, whereas methyidopa has been reported to induce neurotoxic symptoms in some lithium-treated patients.There is a risk of lithium intoxication with simultaneous administration of angiotensin-converting enzyme inhibitors (ACEIs) lithium clearance may be reduced by up to 25%. ° Losartan, an angiotensin II antagonist, was anecdotally reported to induce lithium intoxication. ... 

Combined treatment is necessary in the long-term treatment of essential hypertension. p-Blocker and diuretic properties in a same molecule would present a great interest for hypertension management. Few attempts to synthesize hybrid molecules by combining the structures of a p-adrenoreceptor antagonist and a diuretic were described (Fig. 16.34). A hybrid sulfonamide was achieved by linking the (3-blocker propranolol derivative with the 2-chloroben-zene sulfonamide moiety of mefruside. In prizidilol a typical hydrazino pyridazine core, known for its vasodilator property, is combined with propanolol, leading to a dual vasodilator/(3-blocker. ... 

Van Zwieten PA. An overview of the pharmacodynamic properties and therapeutic potential of combined a- and p-adrenoreceptor antagonists. Drugs 1993 45 509-517. 

Figure 17 Hydrolysis and stereospecific reduction of ketoxime prodrugs of the aryloxypropanolamine P-adrenoreceptor antagonists in the eye.

P-ADRENORECEPTOR ANTAGONISTS [SEDA5, 452 SEDA-32, 363 SEDA-33, 397 SEDA-34, 303 SEDA-35, 351] ... 

The [ -adrenoreceptors antagonists (also called [)-blockers) comprise a group of chiral drugs that are mostly used in the treatment of cardiovascular disorders such as hypertension, cardiac arrhythmia, or ischemic heart disease. Teicoplanin is the chiral selector most exploited for the enantioseparation of this class of compounds, followed by vancomycin. Several P-blockers have been analyzed, particularly in the... 

When using PFT with a neutral selector, it is quite difficult to avoid any entrance of the chiral selector into the ionization source, particularly at a high pH, where EOF is important. The use of BGE at low pH and/or coated capillary to minimize EOF is therefore mandatory. However, the coaxial sheath gas, which generally assists the ionization process, leads to an aspirating phenomenon of the chiral selector in the MS direction. Javerfalk et al. were the first to apply PFT with a neutral methyl-/i-CD for the separation of racemic bupivacaine and ropivacaine with a polyacrylamide-coated capillary and an acidic pH buffer (pH 3). Cherkaoui et al. employed another neutral CD (HP-/1-CD) with a PVA-coated capillary for the analysis of amphetamines and their derivatives. To prevent a detrimental aspiration effect, analyses were carried out without nebulization pressure. Numerous other studies presented excellent results such as the enantioselective separation of adrenoreceptor antagonist drugs using tandem mass spectrometry (MS/MS) the separation of clenbuterol enantiomers after solid-phase extraction (SPE) of plasma samples or the use of CD dual system for the simultaneous chiral determination of amphetamine, methamphetamine, dimethamphetamine, and p-hydroxymethamphetamine in urine. 

Grard, S., Morin, P., Dreux, M., and Ribet, J. P. (2001). Efficient applications of capillary electrophoresis-tandem mass spectrometry to the analysis of adrenoreceptor antagonist enantiomers using a partial filling technique. /. Chromatogr. A 926, 3 — 10. 

Tomozawa et al. (Tomozawa et al., 1995) showed that isoproterenol induces IL-1 (3 mRNA in microglia, but not in astrocytes. This increase was inhibited by propranolol and by a cAMP-dependent protein kinase inhibitor. Similarly, NE, (31- and (32-adrcnorcccptors agonists produce an increase in IL-1 (3 mRNA, which is suppressed by (3i- and (32-adrenoreceptors antagonists (Tanaka et al., 2002). In line with those data, isoproterenol increases IL-la and IL-1 (3 mRNA in microglia (Hetier et al., 1991). On the other hand, these authors also showed that LPS-induced production of IL-1 P protein was inhibited by isoproterenol (Hetier et al., 1991). NE also decreases the production of IL-1(3 induced by LPS in miroglia (Dello Russo et al., 2004) (Madrigal et al., 2005). However, the reasons for these differences among the studies are still not clear. 

Szajerski P, Zielonka J, Sikora A, Adamus J, Marcinek A, Gebicki J, Kozlovski VI, Drelicharz L, Chlopicki S. (2006) Radical scavenging and NO-releasing properties of selected beta-adrenoreceptor antagonists. Free Radical Res 40 741-752. 

Other possibiHties include Ot blockers (36) and calcium antagonists (37). Other unproven agents include the P-adrenoreceptor agonists, phosphodiesterase inhibitors that affect movement of sodium and potassium through cellular channels, and calcium contractile protein sensitizers (38). Any of these agents and the appropriate cellular mechanisms that prevent or slow morphologic alteration in the heart or blood vessels should counteract the aging process. 

Labetalol is a p-blocker with nonselective p- and selective Uj-adreno-receptor antagonist properties. With relatively high doses, labetalol elicits postural hypotension, an undesirable side-effect. Dilevalol is one of the four isomers (R, R) of labetalol that is almost devoid of a-adrenoreceptor activity. Hence, the reduction in peripheral vascular resistance observed for dilevalol occurs via its pj-agonist activity, which is not associated with postural hypotension. This renders dilevalol suitable for physically active hypertensive patients and those who complain of cold extremities (19). However, administration of dilevalol has been reported to be associated with a few reversible cases of hepatiris and jaundice (20). Hence, it is unlikely that this drug will become available as a new p-blocker. 

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