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(E)-8-benzylidene derivatives of 2-methyl-5-(3-hydroxyphenyl)morphans: highly selective ligands for the sigma 2
C M Bertha1, B J Vilner, M V Mattson
1Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
The determination of the structure and function of the sigma receptor subtypes and their physiological role(s) has been impeded by the unavailability of selective ligands. We have developed a new class of sigma subtype selective receptor ligands that are (E)-8-benzylidene derivatives of the synthetic opioid (+/-)-, (+)-, and (-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one (1). The derivatives can be prepared by reaction of 1, (+)-1, and (-)-1 with the appropriate benzaldehyde under Claisen-Schmidt conditions. Incorporation of substituted (E)-8-benzylidene moieties onto the 7-keto precursor of (+)-2-methyl-5-(3-hydroxyphenyl)morphan, (+)-1, produces compounds (-)-2 through (-)-7 (5.8-32.0 nM, sigma 1), which have between a 25- and 131-fold increase in affinity for the sigma 1 receptor subtype relative to the keto precursor (+)-1 (Ki = 762 nM, sigma 1). Compound (-)-2 is the most selective of this group (16-fold) for the sigma 1 subtype versus sigma 2. Substitution of an (E)-8-benzylidene moiety onto the 7-keto precursor of (-)-2-methyl-5-(3-hydroxyphenyl)morphan, (-)-1, produces compounds (+)-2-(+)-9 (6.4-52.6 nM, sigma 2), which have at least a 475-3906-fold increase in affinity for the sigma 2 receptor subtype relative to the keto precursor (-)-1 (Ki = 25 x 10(3) nM). This enhancement of sigma 2 receptor affinity is accompanied by substantial selectivity of all of these dextrorotatory products for the sigma 2 relative to the sigma 1 subtype (32-238-fold), and thus, they are among the most sigma 2 selective compounds currently known. Furthermore, the sigma 1 subtype is highly enantioselective for the levorotatory isomers, (-)-2-(-)-7 (41-1034-fold), whereas the sigma 2 subtype is only somewhat enantioselective for the dextrorotatory isomers, (+)-2-(+)-7 (2.6-9.3-fold). All of these derivatives retain substantial affinity for the mu opioid receptor. Despite the high affinity of the dextrorotatory derivatives for the mu opioid receptor, the high affinity and selectivity for sigma 2 over sigma 1 sites will surely prove beneficial as tools for the delineation of the function and physiological role of sigma 2 receptors.