Alpha1 and alpha2: a selection of the select

TIPS- July 1984 I

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Current awareness

techniques Key developments in pharmacology ally high a2 selectivtty measured in i~lated tissues and high selectivity in radioligand binding studies (Table !). This selectivity of RX 781094 is seen also m tqvo in pithed rats in its markedly preferential inhibition of a,-mediated pressor responses. Since piperoxan (V) itself has little a2-selectivity, the high selectivity of IV presumably derives from the presence of the imidazoline nucleus, a structural component of many ligands active at ot2-adrenoceptors. Even greater selectivity can be seen in 2-alkyl and 2alkoxy substituted derivatives of ILX

Alpha and alpha=: a selection of the select Structure-function studies of drugs active at a-adrenoceptors continue to be exploited to generate ligands with greater selectivity for at- or ot2-receptors. Such iigands may prove to be useful pharmacological tools, perhaps aiding in the definition of the postsynaptic aadrenoceptor types present in vascular smooth muscle. Additionally, it has been suggested that selective ot2-antagonists may represent a novel class of antidepressants. In 1983, several new structures were reported which show significant selectivity its agonists or antagonists at ator ot2-receptors (Fig. 1). The Merck, Sharpe and Dohme group observed that 6-chloro-2-( 1-piperazinyi)pyrazine (I) had significant ot2-selectivity in radioligand binding assays (Table I): this selectivity was enhanced in some fused ring imidazo[1,2-a]pyrazines including 8-(1-piperazinyl)imidazo[l,2-a]pyrazine (II). However, the 2,3-dihydro derivative of II has considerably reduced "2 activity and is a non-selective ligand ~. Simplification of the molecular requirements for selective activity is apparent in the pyridinylpiperazine series- where the parent compound 1-(2-pyridinyl)piperazine (III, X = H) demonstrates considerable a2-selectivity which is further enhanced in the 3-fluoro analog (Ill.

X = F: Table 1). Although the selectivity ratio for ill is reduced in tissue experiments it is still comparable with that of yohimbine and rauwolscine. Combination of the 1,4-benzodioxan and imidazoline nuclei by investigators at Reckitt and Colman ~4' has produced a series amongst which compound IV (Idazoxan: ILK 781094; 2-[l,4-benzodioxan-2-yl]-2-imidazoline) has exception-

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262

781094: thu.~;the 2-MeO derivative shows a ratio of 300 and the 2-isopropenyl derivative a ratio of 1 500 in the rat vas deferens and anococcygeus preparations 5x'. The benz~,.epine structure re-eme~'ges as a selective a2-antagonist in 6-chloro2,3,4,5 -tetr~thydro-3-methyl- 1H -3-benzazepine (VI) synthesized by a group at Smith, Kline and French 7 and shown to have an Ot2:OtI selectivity ratio of approximately 50 (Table 1). Also from Smith, Kiine and French comes 1,2,3,4-tetrahydro - 8 - methoxy - 5 - (methylthio) - 2 naphthalenamine (VII) which has selective arstimulant properties s. As the (-)-enantiomer, VII is some 20- and 80-

T I P S - J u l y 19~t

Huff, J. R., Guam, J. P. Jr, Hunt, C. A., Randall, W. C.. Anderson, P. S., Lotti, V. J., Taylor, D. A. and Clin~-~chmidt,B. V. (1983) J. Med. Chem. 26, 1696-1701 3 Chapleo,C. B., Myers, P. L., Butler, R. C. M., Doxey, J. C., Roach, A. G. and Smith,C. F. C. (1983) J. Med. Chem. 26, 823--831 4 Doxey,J. C., Roach, A. G. and Smith,C. F. C. (1983) Br. J. Pharmac.,I. (1983) 78, 489-505 5 Doxey, J. C., Roach, A. G., Strachan, D. A. D. J. TRIGGLE and Virdee, N. (1983) Br. J. Pharmacol. 79, Department of Biochemical Pharmacology, State 3lip University. of New York, Buffalo, IVY 14620, USA. 6 Doxey, J. C., Roach, A. G., Stillings,M. R., Strachan, D. A., Virdee, N. K. and Welboum, A. P. (1984)Br. J. Pharmacoi. 81,181P lleadblg list 1 Lumma. W. C. Jr. Randall, W. C,, Cresson, 7 DeMarir.is, R. M., Hieble, J. P. and Matthews, W. D. (1983)J. Med. Chem. 26. 1213-1214 E. L., Huff, J. R., Hartman, R. D and Lyon, T, F. (1983)J. Med. Chem. 26, 357-363 8 DeMarinis. R. M. and Hieble, J. P. (1983) 2 Saari. W. S.. Haiczenko, W.. Ki~.,~g,S. W., J. Med. Chem. 26, 121.¢~-i2a8

tbid more potent than norepinephrine and methoxamine respectively in con,racting rabbit ear artery. Furthermore, VII appears to have an (If'or 2 selectivity of at least 300 in this preparation. This also should be a useful agent in the further definition of et-adrenoceptor ~=ubtypes.

Substituted benzimidazoles, a n e w prospective tool for the t r e a t m e n t of peptic ulcer d i s e a s e Histamine H2-receptor antagonists have dominated the field of peptic ulcer therapy for the last six years. It can be predicted that they will survive for quite a while. These aqtagonists are highly specific and block all H2-receptors including those believed to be localized in ~he baso-lateral membrane of the parietal cellL Subsequent parietal cell reactions .remain intact when the H2receptor is; blocked as indicated by the fact that acid.secretion can be stimulated by dibutyryl-cAMP in vitro even in the presence of a histamine H2-receptor antagonist, A new pharmacological principle, mo;e or less circumventing the pharmacological literature, has silently been developed and will be of great interest in peptic ulcer therapy. For several years it was believed that protons are pumped into the gastric lumen by a bicarbonate-stimulated ATPase 2. Recent studies, however, indicated that an ATPase clearly distinguishable from the bicarbonate-stimulated ATPase acts as the parietal cell proton pump. This enzyme is activated in vitro by potassium or closely-related alkafi cations and is referwd to as K +/14+ATPase 3. Enzyme isolation procedures 4"5 and immunofluorescence staining techniques°, have shown that the enzyme is localized in the membrane of the parietal cell secretory canaliculi. The current view of how hydrochloric: acid is secreted into the gastric lumen is expressed diagrammatically in Fig. 1 Very little is known about how this system is controlled. There are now cornl~_~;nds available whi(:h selectively inhibit ~the parietal cell K+EI+-ATPase and leave other ATP-

,'ises unaffected 7"s. These compounds have been developed in the research laboratories of Hiissle in MOindal, Sweden. The prototypes are shown in Fig. 2. Initially the effect of these compounds was studied in isolated rabbit gastric glands 9 and in isolated and enriched guinea-pig parietal cells l°. In either system acid secretion, as measured by the [t4C]aminopyrine uptake and accumulation technique, was inhibited in a concentration-dependent manner, no matter what the applied stimulus was. Thus, acid secretion promoted by dibutyryi c A M P (acting on intracellular protein kinase) or high concentrations of potassium (possibly acting on the proton pump) as well as that promoted by histamine was inhibited. This implies that the locus of action is beyond the protein kinase system. In both the gastric glands and isolated parietal cells, the type of inhibition observed was noncompetitive. However, there is some controversy with regard to the reversiH+

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bility of inhibition. In isolated parietal cell preparations, timoprazole, picoprazole and omeprazole have been shown to be washed out completely l°. This observation finds support from another study: in a pa~ially purified K+/H +ATPase preparation from guinea-pig parietal cells the effect of an almost completely inhibitory concentration of omeprazole could be abolished by subsequent dilution ef the incubate 5. On the other hand, an autoradiographic study with [14C]omeprazole showed radioactivity remaining as long as 16 h after administration in the mouse stomach wall 15. This suggests irreversible binding. The mechanism by which substituted benzimidazoles block the K+/H+-ATPase is unknown. There is some indication that they interact with SH groups of the enzyme. In experimental animals and man omeprazole has been shown to be a powerful and longlasting inhibitor of gastric acid secretion ~]'~2 suggesting that this class of compounds is suitable for the treatment of peptic ulcer disease. Indeed, the first controlled clinical trial (in which 60 mg omeprazole was administered once daily) has resulted in corn,~ I

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