Vibrational modes in the agonist and antagonist action of ligands on the β1-adrenoceptor and some receptor site geometry

A one-dimensional model for the agonist action of phenoxypropanolamine agents on the β1-adrenoceptor can be based on two electronegative receptor sites positioned from known ligand–receptor interactions. One of these sites interacting with the protonated amine moiety of the ligand and associated with the initiation of stimulus action was shown to be consistent with the presence of an anion in a related article. Contraction of the relevant unbound phenoxypropanolamine conformer is required to enhance the charge–charge interaction. The free energy of contraction of the phenoxypropanolamine conformer with consequent movement of the side chain polar moieties to a position more coincident with that of an ethanolamine has been estimated in two parts using minimal basis STO-3G calculations. The unprotonated species was considered adequate for estimating the intrinsic changes in the backbone compression. Movement of the aromatic ring in the one-dimensional axis due to in-plane meta and para hydrogen atom distortion was earlier shown to be consistent with a displacement of 0.1 A with an enthalpy requirement of 2.2 kcal. For the aliphatic side chain, an STO-3G enthalpy estimate of 4.6 kcal was required for a movement of 1.0 A in the position of the protonated amine moiety towards the aromatic ring. Changes in vibrational contributions due to the contraction were small, the entropic contribution being 0.15 kcal, giving a free energy of distortion in the aliphatic side chain of 4.7 kcal. The net movement of the protonated amine and its attendant β-hydroxyl is thus some 1.1 A in the onedimensional axis for an estimated expenditure of 6.8 kcal enthalpy. Since there is an estimated 6–7 kcal enthalpic advantage shown by the side chain's polar interaction in agonist as opposed to antagonist action, this degree of distortion is consistent with the production of a partial agonist. In the dominant axis of the compression model, the phenoxypropanolamine phenyl ring lies some 0.5–0.7 A below that of the nonarenaline conformer. The net lowering of the amine moiety in this axis would therefore be 1.6–1.8 A, but for its raising by 1.9 A due to the presence of the OCH2 moiety. The estimate for the distortion for each of the receptor polar sites for agonist interaction would be less than 0.15 A. In addition, there may be a further 1–2 kcal of free energy still available for further ligand distortion due to the potential amplification of the stimulus signal. The energetics of the model are therefore of the right order in estimating the position of polar receptor sites with good accuracy.