A Marked Change of Receptor Affinity of the 2-Methyl-5-(3-hydroxyphenyl)morphans upon Attachment of an (E)-8-Benzylidene Moiety: Synthesis and Evaluation of a New Class of .sigma. Receptor Ligands

Abstract

The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding enantiomers of 5 and 6 were obtained in > 99% optical purity from the optical isomers of 4, resolved with the O,O'-dibenzoyltartaric acids. The absolute configurations of the enantiomers of 4 were determined by conversion, via Clemmensen reduction, to the enantiomers of 1, the configurations of which are known. The determination of the regioisomer and configurational isomer of 5, with respect to the introduced benzylidene group, was determined from a single-crystal X-ray analysis. 1H NMR data was used to confirm that 6 possessed the same configuration as 5. Radioreceptor binding studies in rat and guinea pig brain preparations revealed that (-)-(1S,5S)-5 displayed an 11-fold decrease in affinity for the opioid mu receptor and an increase in affinity for sigma receptors of 81-fold (low nanomolar affinity) relative to the ketone precursor (+)-(1S,5S)-4. An analogous, albeit less dramatic, trend was seen with compound (-)-(1S,5S)-6. Compounds (-)-(1S,5S)-5 and (-)-(1S,5S)-6 are distinct from the typical sigma-opiates in that they have very low affinity for either PCP sites or muscarinic receptors. The high affinity and selectivity of these novel sigma receptor ligands suggests that they will be valuable for the elucidation of the functional roles of sigma receptors.

Molecular modeling of σ1 receptor ligands: a model of binding conformational and electrostatic considerations

“…These include derivatives of: piperidine and piperazine [17,20,[22][23][24][25][26][27][28][29][30]; alkylamine [18,19,23,[31][32][33]; dextromethorphan [34]; morphan [35]; NANM (SKF10047, N-allyl-N-normetazone) [36,37]; benzoxazolone and benzothiazolone [38]; camphidine [39] and benzamide [40]. Furthermore, various SAR studies of 1 ligands were also performed [3,25,26,[31][32][33][34][35][36]41]. On the other hand, very few 2 selective ligands are known.…”

The σ2 Receptor: A Novel Protein for the Imaging and Treatment of Cancer

“…40 These compounds were identified as part of a structure-activity relationship (SAR) study to improve the affinity of (-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one for μ versus κ opioid receptors. 41 Incorporation of an ( E )-benzylidene moiety into the 8-position of the ring system increased affinity for σ receptors, with the (+)-1 R ,5 R isomer CB-64D ( 1 ) having a 185-fold higher selectivity for σ 2 versus σ 1 receptors whereas the (-)-1 S ,5 R isomer, CB-64L ( 2 ) had a higher affinity for σ 1 than σ 2 receptors (Figure 2). The corresponding 3,4-dichloro analog, CB-184 ( 3 ), had an even higher affinity and selectivity for σ 2 versus σ 1 receptors whereas the corresponding (+)-isomer, CB-182 ( 4 ), displayed a similar affinity for σ 1 and σ 2 receptors.…”

Classes of Sigma2 (σ2) Receptor Ligands: Structure Affinity Relationship (SAfiR) Studies and Antiproliferative Activity

“…Besides that, these (+)-morphans displayed very low affinities for the muscarinic receptors, the PCP binding sites and the other opioid receptors ( and ). Therefore, they emerged as the most 2 subtype selective ligands known for over a decade [18] becoming an important tool for the investigation and characterization of 2 receptors.…”