Theoretical study of the opioid receptor selectivity of some 7-arylidenenaltrexones

A ZINDO/1 quantum-chemical structure-affinity relationship study is presented for the interaction of a group of 7-arylidenenaltrexones with μ, κ and δ opioid receptors. From this work it is concluded that: 1. The internal occupied molecular orbitals are extremely important to regulate receptor affinity and, in the case of the drug-receptor interaction, they seem to play a fundamental role in receptor affinity and selectivity. 2. Receptor selectivity seems to be regulated by subtle electronic differences, sometimes at the same atomic center. 3. In 7-arylidenenaltrexones, phenyl ring D is important for the interaction with all three receptors. Here, atoms 4 and/or 17 are possible targets for modifying receptor selectivity and/or affinity. 4. Reactivity indices of a given atom are affected by substituents placed on atoms that may be very far from it. It is suggested that this may be one of the main reasons to treat the drug-receptor interaction quantum-mechanically.