Crystal structures of .alpha.- and .beta.-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of .mu. opioid receptors

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Abstract
.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 fumaramarate double bond of 1a is more than 2 .ANG. away from that in its epimer 1b and in the wrong orientiation 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.

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