Al-adrenoceptor antagonists

Cocchi, M., Menziani, M.C., Fanelli, F. and De Benedetti, P.G. (1995) Theoretical quantitative structure-activity relationship analysis of congeneric and non congeneric al-adrenoceptor antagonists a chemometric study. Journal of Molecular Structure (Theochem), 331, 79-93. 

Dopamine D2 agonists, Tachykinin NKl antagonists, al Adrenoceptor antagonists, PGE2 antagonists,... 

Balls, T., Andersen, K., Soby, K.K., and Liljefors, T. al Adrenoceptor subtype selectivity 3D-QSAR models for a new class of al adrenoceptor antagonists derived from the novel antipsychotic sertindole./. Mol. Graph. Mod. 2003, 21, 523-534. 

Martin DJ. Preclinical pharmacology of al-adrenoceptor antagonists. Eur Urol 1999 36(Suppl. 1) 35-41. 

Betti, L., Floridi, M., Giannacini, G., Manetti, R, Strappaghetti, G., Tafi, A. andBotta, M. 2003. al-Adrenoceptor antagonists. 5. Pyridazinone-arylpiperazines. Probing the influence on affinity and selectivity of both ortfcj-alkoxy groups at the arylpiperazine moiety and cyclic substituents at the pyridazinone nucleus. Bioorg. Med. Chem. Lett. 13 171-173. 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

Pellejero, T., Monti, J. M., Baglietto, J. et al. (1984). Effects of methoxamine and alpha-adrenoceptor antagonists, prazosin and yohimbine, on the sleep-wake cycle of the rat. Sleep 7, 365-72. 

An SPE cartridge can be used multiple times, especially after the samples are pretreated with protein precipitation. Bourgogne et al. (2005) quantitated talinolol, a p -adrenoceptor antagonist used to treat arterial hypertension and coronary heart disease, in human plasma. The sample was first precipitated with perchloric acid and the supernatant was injected directly. An Xterra MS analytical column (50 x 4.6 mm, 3.5 [m, Waters) with a C18 recolumn filter (4x2 mm, 3.5 /.mi, Phenomenex) and a C8 EC cartridge were chosen. The cycle time was 4.8 min and linear range was 2.5 to 200 ng/mL. Protein precipitation allowed the SPE cartridge to be used for more than 90 injections. 

Idazoxan is an imidazoline compound developed to be a potent and highly selective Oj-adrenoceptor antagonist with little interaction at Oj and P adrenoceptor or other major neurotransmitter receptors. However, like many of the imidazolines that show high affinity for adrenoceptors, idazoxan has equal or higher affinities for the recently identified imidazoline receptors. Imidazoline receptors have been shown to be present in many tissues, including human brain [De Vos et al. 1994], and have been hypothesized to be involved with the regulation of blood pressure and possibly norepinephrine release [Ernsberger et al. 1990]. 

Finally, while on the subject of possible clinical effects of (%2 antagonism, it should be noted that many of the 5-HT, agonists (e.g., buspirone, gepirone, and ipsapirone] that were developed or tested for antianxiety and antidepressant effects are extensively metabolized to l-(2-pyrimidyl]-piperazine, itself an active 0(2-adrenoceptor antagonist (G. Bianchi et al. 1988). Whether this is relevant in vivo in humans remains to be seen. 

Bianchi G, Caccia S, Della Vedove F, et al The alpha-2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite l-(2-pyrimidinyl -piperazine (PMP). Eur J Pharmacol 151 365-371, 1988... 

Elliott HE, Jones CR, Vincent J, et al The alpha adrenoceptor antagonist properties of idazoxan in normal subjects. Chn Pharmacol Ther 36 190-196, 1984... 

Schmidt. M.E., Oshinsky, R.J., Kim, H.G., et al. Cerebral glucose metabolic and plasma catecholamine responses to the alpha (2) adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers. Psvchopharmacologv 146(2), 119-127, 1999. ... 

Ketanserin has a complex pattern of action. It is an antagonist of 5-HT2 receptors and peripheral al adrenoceptors. Although both effects might contribute to a blood pressure lowering effect, it is likely that there is also an additional central component involved. 

Theeuwes, F., Swanson, D. R., Guittard, G., et al. Osmotic delivery systems for the beta-adrenoceptor antagonists metoprolol and oxprenolol Design and evaluation of systems for once-daily administration. Br. J. Clin. Pharmacol. 19 (suppl 2) 69S-76S, 1985. 

It is of interest that idazoxan was tested in Parkinson s disease, although this indication was abandoned for lack of efficacy (F. Colpaert, personal communication). Efaroxan and its active dextro enantiomer dexefaroxan are also potent and selective centrally acting (X2 adrenoceptor antagonists (Bauer et al. 2003 Rizk et al. 2006). Efaroxan was developed for the treatment of chronic neurodegenerative diseases but abandoned because of side effects (P. Sokoloff, personal communication). 

Activation of a2-adrenoceptors in pancreatic p-cells inhibits insulin release, and this effect is blocked by 0C2 adrenoceptor antagonists (Angel and Langer. 1988 Lorrain et al. 1992). A peripherally active 0C2 adrenoceptor antagonist, SL 84.0148, was developed for the treatment of type 11 diabetes (Angel et al. 1992 1996) but was abandoned in Phase 11 (S.Z. Langer, unpublished). 

X2 Adrenoceptor antagonists may increase heart rate as well as blood pressure. These side effects are due to increased release of NA resulting from the blockade of presynaptic terminal 0C2 autoreceptors on peripheral sympathetic neurons (Langer 1981). These cardiovascular side effects are minimal or absent with idazoxan (Schmidt et al. 1997). 

The beneficial effect of mirtazapine in the treatment of depression might be explained by its a2-adrenoceptor antagonistic property. Bupropion and desipramine might be also beneficial in depression because of their ability to increase extracellular NE levels (Femandez-Pastor et al., 2005 Li et al., 2002 Parini et al., 2005 Sacchetti et al., 1999). The beneficial effect of NE in depression can be explained by the excitatory effect of NE on 5-HT neurotransmission and by the direct involvement of NE transmission in anxiety, energy feeling and motivation (Guiard et al., 2008 Stahl, 2000). 

Lennard MS. 3-Adrenoceptor antagonists. In Levy RH, Thummel KE, Trager WF, et al., eds. Metabolic Drug Interactions. Philadelphia Lippincott Williams and Wilkins, 2000 347-358. 

Similar to the theoretical model of Palm et al. [54], based on dynamic surface properties for the prediction of drug absorption into human intestinal Caco-2 cell lines the authors used their molecular dynamics/GRID approach to correlate the absorption of the same set of six P-adrenoceptor antagonists with the coefficients obtained by the water probe at contour level -2 and -3 kcal/mol. 

OshikaT, Ohashi Y, Inamura M, et al. Incidence of intraoperative floppy iris syndrome in patients on either systemic or topical alpha(l)-adrenoceptor antagonist. Am J Ophthalmol 2007 143 150-151. 

The effects of a2 agonists can be reversed with the specific 02 adrenoceptor antagonists yohimbine, tolazoline, atipamezole or idazoxan. Yohimbine is an ct2 antagonist with an a2/ i adrenoceptor selectivity of 60 1. Tolazoline is less 2 specific than yohimbine. Atipamezole has an 2/ai specificity that is 200-300 times that of yohimbine. Atipamezole, at a dose rate of 60 pg/ kg, effectively reverses medetomidine action (plasma levels of 1-1.5 ng/ml) (Bettschart-Wolfensberger et al 1999). Doses of 100-160 pg atipamezole have... 

Ford AP, Arredondo NF, Blue DR Jr, et al. RS-17053 (W - [ 2 - (2-c y c lop rop y I -methoxyphenoxy)ethyl] -5-chloro-a, a-dimethyl- lH-indole-3-ethanamine hydrochloride), a selective a1A-adrenoceptor antagonist, displays low affinity for functional ct -adrenoceptors in human prostate implications for adrenoceptor classification. Mol Pharmacol 1996 49 209-215. 

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