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A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring "open" derivatives display very high affinity for μ and κ receptors and much less affinity for δ. The observation that these target compounds have much higher receptor affinity than the corresponding ring "closed" carboxamides significantly strengthens our underlying pharmacophore hypothesis concerning the bioactive conformation of the carboxamide group.We recently reported the synthesis and exceedingly high μ opioid receptor binding affinity (K i = 0.052 nM) of a novel derivative 1 of 3-desoxy-3-carboxamidonaltrexone 2. 1 The design of 1 was based a strategy whereby the 3-carboxamido group was stabilized in the putative bioactive conformation 1a via an intramolecular H-bond to the adjacent 4-OH donor. The rationale behind this pharmacophore hypothesis arose from the observation that carboxamide derivative 2 had much lower binding affinity than naltrexone (3). 2 This result was in conflict with our other SAR studies where the OH → CONH 2 switch on non-4,5α-epoxymorphinan core opioid structures (e.g., 2,6-methano-3-benzazocines and morphinans) resulted in sustained or enhanced binding affinity. [1][2][3] We recently reported studies where the OH → CONH 2 switch was performed on fifteen additional diverse opioid core structures; results were entirely consistent with our earlier work. 4 These SAR data coupled with the observation that the proton NMR (CDCl 3 ) spectrum of 2 revealed a strong H-bond between the carboxamide NH (as donor) and the neighboring ether oxygen (i.e., 2a) led us to reason that the putative carboxamide bioactive conformation was that as shown in 2 rather than 2a and the compound must pay an energy penalty to adopt the putative bioactive conformation 2 resulting in lower affinity. 1 We also provided strong proton NMR evidence that a) the intramolecular H-bond of 1a was a consequence of the carboxamide acting as acceptor and not as donor (i.e., 1b) and b) the benefit of the 4-OH of 1 was to stabilize the putative bioactive conformation 1a and not via direct contact with the receptor. 1 © 2009 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: +1 518 276 2234; fax: +1 518 276 4887; wentmp@rpi.edu (M. P. Wentland). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure 1. The conformations of the two compounds in the solid state...

The synthesis and evaluation of a series of aryl-containing N-monosubstituted analogues of the lead compound 8-carboxamidocyclazocine were performed to probe a putative hydrophobic binding pocket of opioid receptors. High binding affinity to mu, kappa, and delta opioid receptors was observed for the 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogue.

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