Discovery of an Opioid K Receptor Selective Pure Antagonist from a Library of N-Substituted 4-Methyl-5-(3-hydroxyphenyl)morphans James B. Thomas, † Robert N. Atkinson, † Nivedita Namdev, † Richard B. Rothman, ‡ Kenneth M. Gigstad, † Scott E. Fix, † S. Wayne Mascarella, † Jason P. Burgess, † N. Ariane Vinson, † Heng Xu, ‡ Christina M. Dersch, ‡ Buddy E. Cantrell, § Dennis M. Zimmerman, § and F. Ivy Carroll* ,† Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, Clinical Psychopharmacology Section, NIDA Addiction Research Section, P.O. Box 5180, Building C, 4980 Eastern Avenue, Baltimore, Maryland 21224, and Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 4628 Received February 20, 2002 A library of compounds biased toward opioid receptor antagonist activity was prepared by incorporating N-phenylpropyl-4-methyl-5-(3-hydroxyphenyl)morphans as the core scaffold using simultaneous solution phase synthetic methodology. From this library, N-phenylpropyl- 4-methyl-5-(3-hydroxyphenyl)-7R-[3-(1-piperidinyl)propanamido]morphan [(-)-3b] was identi- fied as the first potent and selective κ opioid receptor antagonist from the 5-phenylmorphan class of opioids. Introduction Since the discovery of three distinct opioid receptors (µ, δ, and κ), researchers studying the underlying mechanisms of opiate addiction have sought highly potent and receptor subtype selective antagonists. 1 While many agonist structures have been discovered for the opioid receptor system, very few structures display- ing potent pure antagonist activity have been identi- fied. 2 The 5-(3-hydroxyphenyl)morphans such as 1a (Chart 1) are one class of compounds that has produced both agonists and antagonists for the opioid receptors. 3,4 These compounds are structurally similar to the trans- 3,4-dimethyl-(3-hydroxyphenyl)piperidine class of opioid antagonists (2a,b) with the exception that they are conformationally rigid as compared to the phenylpip- eridines due to the addition of a bridging ring. While potent antagonists based on the 5-(3-hydroxyphenyl)- morphan scaffold remained an elusive goal for many years, we recently demonstrated that N-phenethyl-9- methyl-5-(3-hydroxyphenyl)morphan (1b) is a highly potent opioid receptor antagonist that is pharmacologi- cally very similar to N-phenethyl-trans-3,4-dimethyl- (3-hydroxyphenyl)piperidine (2a). 5 In a previous paper, we reported the discovery of 4b from the library of compounds based on general struc- ture 4a (Chart 1). 6 Subsequent structure-activity re- lationships (SAR) based on this screening hit led to the discovery of the highly potent and selective κ opioid antagonist JDTic (4c). 7 The discovery that 1b possessed potent antagonist activity at the µ, δ, and κ opioid receptor similar to that available in the 4-phenylpip- eridine series suggested that libraries of compounds (3a) where R 3 contained an amino group located at different distances relative to the rigid morphan structure might act as a κ address moiety and thus bias the library for the opioid κ receptor. 6 As illustrated by general struc- tures 3a and 4a, the libraries differ by the placement of their diversity elements relative to the core antagonist ligand. Thus, if the trans-3,4-dimethyl-(3-hydroxyphe- nyl)piperidine substructure, common to both 3a and 4a, associates with a similar antagonist domain, then the diversity elements affixed to these scaffolds can occupy different regions of the opioid receptor. The use of this dual scaffold strategy was undertaken to provide a more * To whom correspondence should be addressed. Tel: 919 541-6679. Fax: 919 541-8868. E-mail: fic@rti.org. † Research Triangle Institute. ‡ NIDA Addiction Research Section. § Eli Lilly and Company. Chart 1 3524 J. Med. Chem. 2002, 45, 3524-3530 10.1021/jm020084h CCC: $22.00 © 2002 American Chemical Society Published on Web 07/04/2002