Design and synthesis of trans-decahydroisoquinoline derivatives as new tramadol-like ligands

Neuropathic pain is treated with many drug classes - including narcotic analgesics, anticonvulsants, antidepressants and topical anaesthetics – with a limited cost-benefit profile (1). Nucynta ER (extended release Tapentadol) is the newest compound to enter the neuropathic pain market and represents a clinical differentiation from other established treatment options due to its dual mode of action - agonism of the mu opioid receptor (MOR) and noradrenaline reuptake inhibition. Tapentadol is a derivative of Tramadol that are both clinically used analgesics. Multitarget ligands, with an opioid and non-opioid mechanism of action, showed favourable and safety clinical profile in neuropathic pain conditions requiring long-term management (2). So, with the aim to obtain compounds that maintained the mechanism of action of the parental ligands and showed an improved analgesic efficacy, some tramadol-like compounds have been designed and synthesized. In fact, an improved pain relief remains a primary need in chronic pain management. Extensive SAR studies on tramadol and relative derivatives have been performed. Thus, pharmacophoric features and their critical distances have been highlighted to identify a model that represented the interaction with MOR of these series of compounds. Conventional synthetic methods were used to synthesize intermediate and final compounds. Moreover, microwaves (MW) assisted syntheses (CEM Focused Microwave™ Synthesis System, Model Discover) were employed to improve some synthetic routes. Final compounds were purified by flash-chromatography and tested through HPLC analysis (Waters). All intermediates and final products have been characterised through IR (Perkin-Elmer FTIR 1600), 1H- and 13C- NMR (Varian Inova, 200-500 MHz), mass spectroscopy. To design tramadol-like derivatives, it has considered either pharmacophoric features of tramadol (an aromatic ring linked to a quaternary carbon, a two-carbon chain and a basic nitrogen bearing a methyl group) and their relative distances. Thus, it has been synthesized a series of compounds containing the trans-decahydroisoquinoline nucleus (fig.1), in which two pharmacophoric elements of tramadol - the lateral chain and the basic nitrogen - are constrained in a cyclised structure. The constrained structure of trans-decahydroisoquinoline nucleus may exert a positive role by blocking the final compounds in a semi-rigid conformation that could enhance the MOR efficacy. In fact, the overall structure of these new compounds resembles the conformational characteristics of (+)-tramadol, the isomer with major affinities to MOR. Trans-decahydroisoquinoline nucleus synthesis has provided a five-stage approach (3). One-pot synthesis was used to obtain first intermediates. Briefly, in a representative procedure, magnesium ethyl malonate underwent Michael addition to 2-cyclohexenone and the resulting malonate mono ethyl ester intermediate was decarboxylated by McMurry’s procedure. Protection of the relative ketones as ethylene acetal allowed their subsequent conversion into amides. Their successive reduction to amines was performed in about 90% yield with LiAlH4 in THF and resulting amines were undertaken to a Mannich- type cyclization to obtain trans-decahydroisoquinoline nucleus. A further synthetic step was required to obtain final compounds by using Grignard reagents (4). Synthesized derivatives will be pursued in in vitro studies of competition binding in order to determine their affinities for MOR, delta-opioid receptor (DOR) and kappa-opioid receptor (KOR). Moreover, to evaluate the activity versus MOR, DOR and KOR, the new compounds will be assessed by ex vivo assays on pig ileum and rat vas deferens. Finally, in vivo antinociceptive profile in acute and chronic pain animal models could be investigated for most promising derivatives.