β1- and β2-Adrenoceptor antagonist activity of a series of para-substituted N-isopropylphenoxypropanolamines

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Abstract

To further explore the structure-activity relationships of β-adrenoceptor (β-AR) antagonists, a series of 25 para-substituted N-isopropylphenoxy-propanolamines were synthesised, nine of which are new compounds. All have been examined for their ability to antagonise β1-ARs in rat atria and β2-ARs in rat trachea. Substitution in the para-position of the phenyl ring is thought to confer β3-specificity and the selectivity of these compounds for the β1-AR ranges from 1.5–234. None of the compounds tested were selective for the β2-AR. Of the 25 compounds studied, 22 had reasonable (pA2 > 7) potencies for the rat β1-AR. Only compound 1 displayed reasonable (pA2 > 7) potency for the rat β2-AR. Twenty two compounds were used as the training set for comparative molecular field analysis (CoMFA) of antagonist potency (pA2) at the rat β1- and β2-ARs. The inclusion of a number of additional physical characteristics improved the QSAR analysis over models derived solely using the CoMFA electrostatic and steric fields. The final models predicted the β1- and β2-AR potency of the compounds in the training set with high accuracy (r2 = 0.93 and 0.86 respectively). The final β1-AR model predicted the β1-potencies of two out of the three test compounds, not included in the training set, with residual pA2 values < –0.14, whereas the test compounds were not as well predicted by our final β2-AR model (residual pA2 values < –0.38).

Introduction

β-Adrenoceptors (β-ARs) are members of the large family of G-protein coupled receptors [1], [2], [3], [4]. It has been established so far that there are at least three β-AR subtypes, designated the β1-, β2- and β3-ARs [5], [6], [7]. N-Isopropylphenoxypropanolamine ( figure 1, R = H) is considered to be a non-selective β-AR antagonist. Many structure-activity studies in the past have focused upon the N-isopropylphenoxypropanolamine core structure with substitutions in the ortho and/or meta positions [8], [9]. However, the effects of para-substituents upon the β-blocking activity of this core structure have received less attention [10], [11], [12]. Previous work by us [10], [13] and others [11], [12], [14], [15] has established that high β1-AR selectivity and potency can be achieved by para-substitution of the phenyl ring and/or appropriate substitution of the phenoxypropanolamine amino group (e.g. -ethyl-3-(4-hydroxyphenyl)urea [13]).

To further examine the effect of para-substitution upon both β1- and β2-AR selectivity and potency, we have synthesised a series of para-substituted N-isopropylphenoxypropanolamines. Nine of these compounds are new (6, 7, 9, 10, 15, 16, 18, 20 and 22), that is to say that a chemical abstracts structure database search indicated that these compounds have not been previously reported. Eleven previously reported compounds (1, 2, 3, 4, 5, 8, 12, 14, 19, 23 and 25) and five commercially available compounds (11 (metoprolol), 13 (H 87/07), 17 (betaxolol), 21 (RO 31-1118) and 24 (cicloprolol)) have also been synthesised and included in the study in order to obtain comparative pharmacological data in the rat. All of these compounds have been examined in our laboratory for their ability to antagonise β1-ARs in rat atria and β2-ARs in rat trachea, which are well established as sources of the β1- and β2-AR subtypes respectively [16]. The synthesis and structure-activity relationships, using comparative molecular field analysis (CoMFA), of these para-substituted N-isopropylphenoxypropanolamines are presented here.

Section snippets

Chemistry

All compounds were prepared as their racemic mixtures by the general procedure shown in  figure 2. It has been established for simple phenoxypropanolamines that the S-isomer is the active isomer, with little β-AR activity residing with the R-isomer [17], [18], [19]. Resolution of the racemate into the individual isomers or stereospecific synthesis was therefore not carried out. The corresponding phenols A reacted under aqueous alkaline conditions with epichlorohydrin to produce the epoxides B.

Pharmacology

All compounds were evaluated for their ability to antagonise β1- and β2-ARs in rat atria and tracheal rings respectively. Cumulative concentration-response curves were obtained in each preparation as described by Van Rossum [36] and curves were fitted by computer analysis according to the method of Zabrowsky et al. [37] using the sigmoidal fit function of the Origin graphics package [38]. The antagonist potencies, or pA2 values, were calculated using equation 1 [39] and represent the mean ± SE

Isolated tissue preparations

Functional potencies of compounds 125 for inhibiting (-)-isoprenaline-induced: (i) β1-AR mediated chronotropic effects in spontaneously beating rat atria; and (ii) β2-AR mediated relaxation of rat tracheal chain previously contracted with 1 μM carbachol are listed in  table II. The unsubstituted reference compound 1 had a high potency at both the β1-AR (pA2 = 8.09) and β2-AR (pA2 = 7.47). Para-substitution reduced the potency of the compounds for both β1- and β<§>2-ARs (compounds 211, 1315,

Discussion

The aim of this study was to determine the optimal structural requirements of para-substituted N-isopropylphenoxypropanolamines to maximise antagonist potency and selectivity for β1-ARs. The study also provides information on the extent to which the CoMFA derived models of the rat β1- and β2-ARs differed for a series of para-substituted β-AR antagonists. Although para-substitution generally reduced antagonist potency at both β1- and β2-ARs, differences did exist between the two models. For both

General

Melting points were determined using a manual Gallenkamp electrothermal apparatus (range 0–200 °C) in glass capillary tubes and are uncorrected. IR spectra were recorded on a Perkin-Elmer FT IR 1600. NMR spectra were recorded on a Varian Associates EM 360 spectrometer and are expressed in δ using TMS (tetramethyl silane) as reference. Mass spectra were recorded on a Finnigan 4000 series GC/MS Mass spectrometer or a Thermo Instruments GCQ Mass spectrometer using methane gas as the ionising

Acknowledgements

The authors would like to thank Ms. Leanne Styan for her technical assistance and Dr Margaret Wong for her helpful comments. This work was supported by a grant from the National Health and Medical Research Council of Australia.

References (51)

  • P.A Greenidge

    Pharm. Acta Helv.

    (1994)
  • M Lafontan et al.

    J. Lipid Res.

    (1993)
  • S.N.S Louis et al.

    Eur. J. Pharmacol.

    (1999)
  • T.L Nero et al.

    J. Mol. Struct. (Theochem.)

    (1993)
  • B.R Zaborowsky et al.

    J. Pharmacol. Methods

    (1980)
  • C.D Strader et al.

    J. Biol. Chem.

    (1989)
  • J Ostrowski et al.

    Ann. Rev. Pharmacol. Toxicol.

    (1992)
  • A.D Strosberg

    Prot. Sci.

    (1993)
  • L.J Emorine et al.

    Science

    (1989)
  • T.J Frielle et al.

    Proc. Natl. Acad. Sci. USA

    (1987)
  • B.K Kobilka et al.

    Proc. Natl. Acad. Sci. USA

    (1987)
  • G.M Donne-Op Den Kelder et al.

    J. Med. Chem.

    (1988)
  • M.R Linschoten et al.

    J. Med. Chem.

    (1986)
  • J.B Ball et al.

    J. Med. Chem.

    (1992)
  • J.J Baldwin et al.

    J. Med. Chem.

    (1986)
  • P.J Machin et al.

    J. Med. Chem.

    (1984)
  • Berthold R., Louis W.J., US Patent, US 4, 425, 362,...
  • M.L Hoefle et al.

    J. Med. Chem.

    (1975)
  • M.S Large et al.

    J. Med. Chem.

    (1982)
  • A.H Beckett

    Fortschr. Arzneim. Forsch.

    (1959)
  • L.H Easson et al.

    Biochem. J.

    (1933)
  • Brandstrom A.E., Carlsson P.A.E., Carlsson S.A., Corrodi H.R., Ek L., Ablad B.A.H., US Patent, US 3928601,...
  • Carlsson P.A.E., Brandstrom A.E., Lamm B.R., Ablad B.A.H., Carlsson S.A.I., Corrodi H.R., Ek L., DE Patent, DE 2020864,...
  • A.F Crowther et al.

    J. Med. Chem.

    (1969)
  • M Erez et al.

    J. Med. Chem.

    (1978)
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