Long-range substituent effects in morphine-type agonists and antagonists: A possible explanation for some opiate anomalies
✍ Scribed by Vera M. Kolb
- Publisher
- John Wiley and Sons
- Year
- 1979
- Tongue
- English
- Weight
- 614 KB
- Volume
- 68
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
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.