Diaryldimethylpiperazine ligands with μ- and δ-opioid receptor affinity: Synthesis of (+)-4-[(αR)-α-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide and (−)-4-[(αR)-α-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide

Add time:09/26/2019    Source:sciencedirect.com

We have explored the synthesis of compounds that have good affinity for both μ- and δ-opioid receptors from the (αR,2S,5S) class of diaryldimethylpiperazines. These non-selective compounds were related to opioids that have been found to interact selectively with μ- or δ-opioid receptors as agonists or antagonists. In our initial survey, we found two compounds, (+)-4-[(αR)-α-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (14) and its N–H relative, (−)-4-[(αR)-α-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (15), that interacted with δ-receptors with good affinity, and, as we hoped, with much higher affinity at μ-receptors than SNC80. The relative configuration of the benzylic position in (+)-4-[(αR)-α-(4-allyl-(2S,5S)-dimethyl-1-piperazinyl)-(3-methoxyphenyl)methyl]-benzyl alcohol (10) was determined by X-ray crystallographic analysis of a crystal that was an unresolved twin. The absolute stereochemistry of that benzylic stereogenic center was unequivocally derived by the X-ray crystallographic analysis from the two other centers of asymmetry in the molecule that were known. Those were established from the synthesis via a dipeptide cyclo-l-Ala-l-Ala in which the absolute stereochemistry was established.

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