The stereoselectivity of the ‘single drug binding site’ of human α1-acid glycoprotein (orosomucoid)

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Abstract
The stereoselective binding of six pairs of basic, one pair of acidic drug enantiomers, and one pair of diastereomers to human α1-acid glycoprotein was investigated by means of competition experiments against [3H]propranolol- or [14C]nicardipine-labelled binding sites using equilibrium dialysis to separate free from bound marker ligand. The affinity constants (Ka) for association of [3H]propranolol and [14C]nicardipine with α1-AGP were 1ṁ 2 ± 0ṁ6 times 105M−1 and 3ṁ4 ± 1ṁ4 times 105M−1, respectively, and control binding amounted to 57 ± 7 and 91 ± 2%, respectively. The following selectivity factors, calculated as the ratio of the higher over the lower enantiomer concentrations displacing 15% of control radiomarker binding (IC15***-value), were obtained against propranolol and nicardipine: (-)-/(+) propranolol: 1ṁ9 and 1ṁ7.; (+)-/(-)-disopyramide: ***2ṁ8 and 1ṁ4; (+)-/(-)-verapamil: 1ṁ6 and 1ṁ9; (+)-(S)-/(-)-(R)-202-791, a dihydropyridine derivative: 2ṁ6 and 2ṁ0; (-)-/(+)-asocainol: 1ṁ7 and 3ṁ0; (+)-/(-)-tilidine: 1ṁ1 and ã2; (-)-(S)-/(+)-(R)- warfarin: 1ṁ6 and 2ṁ4; (±)-cis/(±)-trans-trans-tilidine: 1ṁ7 and 1ṁ8. When the calculation of radioligand-free fractions is also taken into account, it is apparent that only the tilidine isomers show no selectivity at propranolol-marked, and the disopyramide isomers at nicardipine-marked α1-AGP-binding sites, in all other cases, a weak selectivity is detectable, which is, however, far below the values obtained for most neurotransmitter receptors. It is concluded that the single drug binding site of α1-AGP is only slightly stereoselective and that the stereoselective binding of the drugs investigated is probably of no clinical consequence.

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