Crystal structures of alpha- and beta-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of mu opioid receptors.
alpha- and beta-funaltrexamine (alpha- and beta-FNA, 1a and 1b) are naltrexone derivatives differing only in chirality at C(6). Both epimers bind to mu opioid receptors in GPI and MVD preparations, but only the beta-epimer irreversibly blocks these receptors in both preparations. In an effort to investigate the reasons for this difference, we have determined the molecular structures of 1a and 1b by X-ray diffraction techniques. The two epimers have almost identical conformations in the fused ring system except for ring C, which is observed in a twist-boat conformation in alpha-FNA and a chair in beta-FNA. As a result the electrophilic fumaramate moieties are equatorial in both structures and orthogonal to one another when the fused rings are superimposed. In the crystal structure of beta-FNA there is a close intermolecular contact between a phenolic oxygen and the fumaramate double bond that can serve as a model for nucleophilic attack on the fumaramate group. When 1a and 1b are superimposed, the fumaramate double bond of 1a is more than 2 A away from that in its epimer 1b and in the wrong orientation for nucleophilic attack from the proposed direction to take place. The results of this study are consistent with a model that postulates the involvement of two consecutive recognition steps leading to the irreversible blockage by beta-FNA (Sayre, L. M.; Larson, D. L.; Fries, D. S.; Takemori, A. E.; Portoghese, P. S. J. Med. Chem. 1983, 26, 1229) and underscores the importance of the second recognition step in conferring selectivity in the Michael addition of a nucleophile to the fumaramate group.
J F
JF
Griffin
D L
DL
Larson
P S
PS
Portoghese
D003461:Crystallography; D007536:Isomerism; D008958:Models, Molecular; D009271:Naltrexone / Q000031:analogs & derivatives*; D011487:Protein Conformation; D014961:X-Ray Diffraction
D009271:Naltrexone; C024524:beta-funaltrexamine