Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans.

The design of enantiopure stereoisomers of N -2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N -cinnamyl moiety, and N -propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N -2-phenylcyclopropyl methyl moieties, N -cinnamyl, and N -propyl substituents). The synthesis of the eight enantiopure N -2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans ( N -E and Z-cinnamyl compounds, and N -propyl compounds) was accomplished. The synthesis started from common intermediates (3 R ,6a S ,11a S )-10-methoxy-1,3,4,5,6,11a-hexahydro-2 H -3,6a-methano-benzofuro[2,3- c ]azocine (+)-6 and its enantiomer, (3 S , 6a R , 11a R ) - (-)-6 , respectively. The enantiomers of ±-6 were obtained through salt formation with ( S )-(+)- and ( R )-(-)- p -methylmandelic acid, and the absolute configuration of the ( R )-(-)- p -methylmandelate salt of (3 S , 6a R , 11a R ) - (-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N -(2-phenylcyclopropyl)methyl derivatives, 2-( E )-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N -phenethyl ortho-c oxide-bridged phenylmorphan ( (-)-1 ), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ( (+)-17 ), and the N-phenylpropyl derivative ( (-)-25 ) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N -2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ( (+)-17 ). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC 50 = 6.92 nM).