Journal of Medicinal Chemistry p. 2970 - 2978 (1992)
Update date:2022-07-29
Topics:
Vecchietti
Clarke
Colle
Dondio
Giardina
Petrone
Sbacchi
This study describes the synthesis of a series of novel substituted 1- (aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the κ opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for κ opioid receptors (K(i) κ = 0.09 nM) and a (K(i) μ/K(i) κ ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the μ opioid receptor. On the other hand, the correlation between binding affinity to κ opioid receptor and antinociceptive activity was statistically significant.
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