Baker, Jillian G.

Mistry, Shailesh N.

Name not available

The effect of the N-alkyl moiety on the interaction of pindolol analogues with the two agonist conformations of the human β1-adrenoceptor

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Mistry, Shailesh N. and Baker, Jillian G. (2016) The effect of the N-alkyl moiety on the interaction of pindolol analogues with the two agonist conformations of the human β1-adrenoceptor. In: British Pharmacological Society 6th Focused Meeting on Cell Signalling 2016, 18-19 Apr 2016, Leicester, UK. Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/38648/1/vol14issue1abst011p.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.uk  Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol14Issue1abst011P.pdf   The effect of the N-alkyl moiety on the interaction of pindolol analogues with the two agonist conformations of the human β1-adrenoceptor  There are two active conformations of the β1-adrenoceptor (AR): a high affinity conformation (HAC) where responses are readily inhibited by antagonists and a low affinity conformation where agonist responses are relatively resistant to antagonism (1). Some ligands, e.g. pindolol, stimulate both conformations (2). Analogues of pindolol were synthesised to examine the contribution of the N-alkyl moiety to activation at each conformation of the human β1-AR. 3H-CGP 12177 whole cell binding and CRE-SPAP reporter gene assay were examined in cells stably expressing the human β1-AR as previously described (2).     R1/R2 Log KD n Log EC501 Log EC502 % site 1 % isop max npindolol  -8.67±0.04 7 -8.86±0.18 -6.32±0.32 51.6±3.6 74.8±10.2 6 1a  -9.40±0.04 10 -9.16±0.11 -6.51±0.13 55.8±4.3 77.0±5.4 8 1b H -7.70±0.04 6 -8.16±0.08 -5.84±0.12 56.5±7.5 69.6±4.2 6 1c  -7.78±0.05 6 -8.21±0.09 -5.69±0.19 43.2±6.5 64.6±5.3 8 1d  -8.77±0.04 6 -8.96±0.13 -6.39±0.20 50.0±3.5 67.2±7.3 9 1e  -8.37±0.03 6 -8.50±0.10 -5.92±0.09 48.5±3.5 70.2±5.9 8 1f  -8.26±0.04 5 -8.41±0.07 -5.88±0.08 44.6±3.4 71.5±8.1 7 1g  -9.82±0.04 10 -9.19±0.14 -6.70±0.34 65.0±4.5 83.2±6.5 8 1h  -8.74±0.04 6 -8.84±0.10 -6.25±0.10 42.7±3.2 72.7±5.1 8 1i  -8.40±0.06 6 -8.93±0.09 -6.35±0.12 58.3±4.1 73.9±7.1 7 1j  -8.30±0.06 6 -8.45±0.05 -6.01±0.08 41.8±3.0 76.1±7.7 8 1k  -9.01±0.05 9 -9.09±0.08 -6.38±0.30 58.2±7.1 81.1±9.2 6 1l  -7.64±0.03 6 -8.05±0.06 -6.01±0.08 53.4±5.8 66.7±9.7 6 1m  -9.54±0.05 6 -9.62±0.11 -6.99±0.21 64.2±6.4 72.7±6.9 7 2a H No binding 4 No response    8 2b  No binding 4 No response    8  Table. Log KD values from 3H-CGP12177 binding and log EC50 values and % maximum isoprenaline responses from CRE-SPAP production. Values are mean±sem of n separate experiments   Ligand affinity for the HAC was affected by the nature of the N-alkyl moiety. Whilst an amine moiety was essential for receptor interaction, sterically small amine groups (e.g. 1b, 1c) gave lower affinity. Steric bulk near to the amine or a distant aromatic group, maintained high affinity for the HAC in addition to agonist activity at both conformations (1a, 1g, 1h, 1k, 1m).  The nature of the N-alkyl moiety does not appear of importance in agonist stimulation at either conformation of the β1-AR.   (1) Kaumann and Molenaar (2008). Pharmacol. Ther. 118: 303–336. (2) Baker et al. (2003). Mol. Pharmacol. 63: 1312–1321. NHO NHOHpindololNHO2a-bONHO1b-mO(S)OHNHR2 R1NHO(S)NHOH1aO∗∗∗∗∗∗∗∗∗∗OO∗∗

The effect of the N-alkyl moiety on the interaction of pindolol analogues with the two agonist conformations of the human β1-adrenoceptor

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