SYNTHESIS AND BIOLOGICAL EVALUATION OF 14-ALKOXYMORPHIN ANS. 14.1 14-ETHOXY-5-METH YL SUBSTITUTED INDOLOMORPHINANS WITH 60PIOID RECEPTOR SELECTIVITY

The 5-methyl and 14-ethoxy substituted analogues (compounds 2 - 4) of the 6 opioid receptor antagonist naltrindole showed similar selectivity when compared with the reference drug. Compound 2 was a 6 receptor antagonist in the mouse vas deferens preparation (MVD) exhibiting considerably higher selectivity ratios than naltrindole, while compound 4 was found to be a full and potent 8 receptor agonist in the MVD. © 1997, Elsevier Science Ltd. All rights reserved. Naltrindole (NTI; 1) is a non-peptidic 8 opioid receptor antagonist which is widely employed. 2-4 Interestingly, this compound exhibits potent immunosuppressive effects. 5-7 The conformationally constrained indolic benzene moiety is suggested as a key "address" component affording selectivity by increasing 6-affinity and reducing affinity for g and ~ opioid receptor sites. 3 In an attempt to improve on the selectivity of naltrindole, to develop potent 8 agonists and to uncover structure-activity relationships in this series of compounds we decided to prepare indolomorphinans with a 14-alkoxy substituent and a 5-methyl substituent, from the corresponding morphinan-6-ones by Fischer indole synthesis. 14-Alkoxy substitutents on morphinans are reported to improve receptor affinity providing potent agonists or antagonists depending on the substituent at the nitrogen. 8 Many of these compounds interact preferentially with get opioid receptors (e.g. the B-selective opioid receptor antagonist cyprodime 9 and derivatives 10,11 ).