title: Substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines: a novel class of very potent antinociceptive agents with varying degrees of selectivity for kappa and mu opioid receptors.
abstract: 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 kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.
authors.affiliation: Zambeletti Research Laboratories, Baranzate, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: R
authors.initials: R
authors.lastname: Colle
authors.forename: G
authors.initials: G
authors.lastname: Dondio
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: G
authors.initials: G
authors.lastname: Petrone
authors.forename: M
authors.initials: M
authors.lastname: Sbacchi
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000700:Analgesics; D007546:Isoquinolines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu