Baker, Jillian G.

Fischer, Peter M.

Gardiner, Sheila M.

Hill, Stephen J.

Kellam, Barrie

Mistry, Shailesh N.

Nottingham ePrints

Baker, Jillian G. and Mistry, Shailesh N. and Fischer, Peter M. and Hill, Stephen J. and Gardiner, Sheila M. and Kellam, Barrie (2012) In vitro and in vivo analysis of a novel highly selective β1-adrenoceptor partial agonist. In: British Pharmacological Society 4th Focused Meeting on Cell Signalling, 23-24 April 2012, Leicester, UK. Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/38643/1/vol10issue1abst024p.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence.  For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdfA note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukProceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol10Issue1abst024P.pdf  In vitro and in vivo analysis of a novel highly selective β1-adrenoceptor partial agonist. Jillian Baker, Shailesh Mistry, Peter Fischer, Stephen Hill, Sheila Gardiner, Barrie Kellam. university of Nottingham, Queen's Medical Centre, NG7 2UH, UK β-adrenoceptor antagonists (β-blockers) are widely used and save lives in people with heart disease due to blockade of β1-adrenoceptors in the heart.  Unfortunately, current β-blockers have poor β1 vs β2-adrenoceptor selectivity and are therefore contraindicated in people with asthma due to their bronchoconstrictor effects via the β2-adrenoceptors in the lungs.  This means that people with both asthma and heart disease are unable to take these life prolonging drugs.  We have previously investigated current β-blockers and found them to have poor selectivity in both cellular assays and in whole animals (Baker et al., 2011).  We therefore initiated a programme to develop highly selective β1-antagonists.  Here we report a novel and highly selective partial agonist for the  1-adrenoceptor: SM64 1-{2-[(3-{4-[2-(cyclopropylmethoxy)ethoxy]phenoxy}-2-hydroxypropyl)amino]ethyl}-3-(4-hydroxyphenyl)urea.  The pharmacological properties of SM64 were investigated using 3H-cAMP accumulation in cells stablyl expressing the human β1 and β2-adrenoceptors and in conscious, atropine-treated freely moving, adult male Sprague-Dawley rats, instrumented for measurement of heart rate (β1) and hindquarters conductance (β2) as previously described (Baker et al., 2011).  At the human β1-adrenoceptor, SM64 stimulated an increase in 3H-cAMP accumulation (log EC50 = -8.05 ± 0.04, 51.7 ± 1.7% maximum isoprenaline, n=5).  It behaved as a typical partial agonist, inhibiting cimaterol agonist responses to give a log KD of -7.76 ± 0.06 n=15 (by the partial agonist method of Stephenson, 1956).  Even at maximal concentrations (10µM, stimulation 9.3 ± 0.09% isoprenaline maximum, n=5) it caused minimal shift of the cimaterol concentration response curve at the human β2-adrenoceptor giving a log KD of -5.01 ± 0.07 (n=5).  SM64 is therefore 457 times β1 over β2 selective.  In conscious rats, SM64 (2mg/kg bolus, 1mg/kg/h infusion) caused an increase in basal heart rate  (from 424 ± 9 bpm to 465 ± 3bpm = 44% of the response to 120ng/kg/min isoprenaline, n=4 animals) in keeping with its partial agonist actions observed in the cell studies. Furthermore SM64 significantly inhibited the β1-mediated heart rate responses to isoprenaline (at 12, 40 and 120ng/kg/min) whilst having no effect on the β2-mediated hindquarters response (n=4 rats), consistent with its β1-selectivity.  In conclusion, SM64 is a high affinity β1-adrenoceptor partial agonist as demonstrated in cell studies and in conscious rats.  A molecule of this selectivity or greater, devoid of partial agonist effects, could prove a very useful therapy for people with heart disease and asthma.  Baker et al., 2011 FASEB J 25: 4486-4497 Stephenson 1956 Br J Pharmacol 11: 5109-5116  

In vitro and in vivo analysis of a novel highly selective β1-adrenoceptor partial agonist.

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In vitro and in vivo analysis of a novel highly selective β1-adrenoceptor partial agonist.

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