HUPRINETACRINE HYBRIDS AS A NOVEL FAMILY OF MULTI-TARGET DRUG CANDIDATES AGAINST ALZHEIMER’S AND PRION DISEASES

Several years ago, a short series of racemic huprine-tacrine hybrids was developed as a new class of dual binding site acetylcholinesterase (AChE) inhibitors. These compounds consisted of: i) a unit of huprine Y, a compound with one of the highest affinities for the active site of AChE yet reported, ii) a unit of tacrine, a compound with known affinity for the peripheral site of AChE, and iii) a linker of appropriate length to allow simultaneous binding to both the active and peripheral sites of the enzyme. Recently, the series of huprine-tacrine hybrids has been extended with the synthesis of shorter and longer homologues. Also, the two enantiomers of two of the most potent racemic huprine-tacrine hybrids have been independently synthesized from readily available (-)- and (+)-huprine Y, and their binding mode has been studied by molecular dynamics simulations. Moreover, additional pharmacological and pharmacokinetic studies have been undertaken. Among other properties, some huprine-tacrine hybrids have been shown to be able to significantly inhibit the AChE-induced A-beta and prion peptide aggregation, two key pathogenic processes involved in AD and in prion diseases, and seem to be able to cross the blood-brain barrier.