Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

• Main Authors: Gerardo Byk, Hadar Eini, Hagit Elhawi, Amos Douvdevani
• Format: Article
• Language: English
• Published: MDPI AG 2012-06-01
• Series: Molecules
• Subjects: sepsis; IL-6; TNF-α; thermal rearrangement; α-amino-ketone; microwave
• Online Access: http://www.mdpi.com/1420-3049/17/6/6784

Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the <em>N</em>-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6) sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to a-aminoketones in parallel arrays. One of the analogues (compound <strong>6e</strong>) displayed high activity in down-regulating the levels of IL-6 and TNF-α<em> in vivo</em> as compared to ketamine.