Divalent metal ions in the pharmacodynamics of morphine-like opiates

Abstract

Paramagnetic Mn(II) ions were used to sample the interaction of morphine-like opiates with divalent metal ions, which are known, especially Ca ++, to be involved in the mechanisms of drug dependence and tolerence. The motional correlation time of the opiate molecule in aqueous solution was determined by selective proton irradiation methods (τ c = 7 × 10 −10 sec at 22 °C) and a preferred cis conformation of H 5 and H 6 protons was inferred. The water proton relaxation rates at different metal to ligand ratios were used to evaluate the equilibrium constant (K ass = 10 −2 M −1) by assuming a dipolar only interaction with T −1 1p modulated by rotational tumbling of the complex (see figure). The temperature dependence of T −1 1p was measured (Table I) in the range 25–60 °C: it turned out that H 1, H 2, H 5, H 7 and H 8 proton relaxation rates were in the fast exchange region, while the −NCH 3 protons were undergoing slow exchange from the metal coordination sphere. ▪ t001 Temperature Dependence of T −1 1p of Morphine Protons. [Morphine] = 0.05 M, [Mn ++] = 0.1 m M, pD = 7. 1000/ T (K −1) T −1 1p (sec −1) H 5 −NCH 3 3.00 0.10 0.24 3.10 0.22 0.13 3.20 0.37 0.05 3.25 0.42 0.04 3.30 0.50 0.07 3.35 0.56 0.12 As consequence, metal-proton distances could be calculated for almost all the protons considered and it was shown that simultaneous binding to the two −OH groups was consistent with the similar measured magnitudes of the MnH 1, MnH 2, MnH 7 and MnH 8 vectors (r is in the range 3.01 – 3.16 Å). H 5 was found to be the nearest proton to the metal ion ( r = 2.84 Å). The temperature dependence of T − 1p of the -NCH 3 methyl protons was taken to evaluate the thermodynamic functions for the exchange process from the metal coordination sphere (k off = 2.25 × 10 4 sec −1, Δ H ≠ = 14.1 kcal/mol, ΔS ≠ = 7.2 e.u.). The structural and kinetic information was used to suggest that interaction with divalent metal ions is characterized, for morphine-like opiates, by an almost exclusively enthalpic barrier due to binding to charged OH groups. Such interaction can be relevant either in modulating the interaction of divalent metal ions with external groups in membranes or in affecting the receptor-opiate interaction modes.