Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of alpha 7 nicotinic receptors with analgesic activity

作者：Balsera Beatriz; Mulet Jose; Sala Salvador; Sala Francisco; de la Torre Martinez Roberto; Gonzalez Rodriguez Sara; Plata Adrian; Naesens Lieve; Fernandez Carvajal Asia; Ferrer Montiel Antonio; Criado Manuel; Perez de Vega Maria Jesus; Gonzalez Muniz Rosario^*

来源：European Journal of Medicinal Chemistry, 2018, 143: 157-165.

DOI：10.1016/j.ejmech.2017.10.083

• Diphenylpropanones
• Prodrugs
• Diketopiperazines
• DDP-IV
• alpha 7 nicotinic receptors
• Allosteric modulation

alpha 7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of alpha 7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2',5',4-trihydroxy-1,3-diphenylpropan-1-one 3, showed significant antinociceptiye activity in in vivo assays. The best compound, 21, displayed a better profile in the analgesia test than its parent compound 3, exhibiting about the same potency but long-lasting effects.

• 出版日期2018-1-1