LONG-RANGE SUBSTITUENT EFFECTS IN MORPHINE-TYPE AGONISTS AND ANTAGONISTS - POSSIBLE EXPLANATION FOR SOME OPIATE ANOMALIES

Anomalous variations in the pKa values of variously substituted morphine‐type agonists and antagonists are interpreted as a reflection of long‐range substituent effects operating in these molecules. Based on the operation of long‐range effects, a mechanism is proposed by which substitution into the N‐normorphine portion of morphine‐type agonists and antagonists changes the activity of the parent molecule. Thus, a remote substituent would distort the whole molecule via a conformational transmission effect and thereby (a) change the fit between the opiate and its receptor; (b) change the electron density distribution throughout the molecule and, therefore, at the nitrogen; (c) modify the directionality of the lone‐electron pair on the nitrogen; and (d) affect the pKa of the drug. The operation of long‐range effects as proposed here could account for some of the anomalous changes in opiate activity effected by substitution into the parent molecule. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company