A New Concept on the Mode of Interaction of Narcotic Analgesics with Receptors

Existing data on the relationship between molecular geometry and narcotic analgesic activity has been interpreted in terms of differing modes of analgesic-receptor interactions. A method for detecting similarities or differences in molecular binding modes has been accomplished by comparing the variation of activity in two or more different series of compounds when identical changes of the N-substituent are made. A parallel change in activity is suggestive of similar binding modes while a nonparallel relationship is indicative of dissimilar interactions. This method has been extended quantitatively to demonstrate the existence of a linear free-energy relationship when binding modes are similar. The value of the slopes from such a relationship are approximately unity. This suggests that, when compounds in two different series interact with the receptors in a similar fashion, identical substituents contribute to the binding by a similar mechanism. The concept of three-point interaction and possible pitfalls inherent in its applicability to the interaction of analgesics with receptors is discussed.