Long-range substituent effects in morphine-type agonists and antagonists: a 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.
D000700:Analgesics; D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009270:Naloxone / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
D000700:Analgesics; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine