Huprine

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Badia et al. designed and synthesized more than 30 huprines, which are the tacrine-HA hybrids of the 4-aminoquinoline moiety of tacrine combined with the bridged carbobicychc moiety, without the ethylidene substituents, of HA. Pharmacological studies of these compounds demonstrated that they are a novel class of potent and selective AChEIs. 3-Chloro-substituted huprines 49a and 49b are the... 

Camps, R Cusack, B. Mallender, W. D. El Achab, R. Morral, J. Munoz-Torrero, D. Rosenberry, T. L. Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer s disease. Mol. Pharmacol, 2000, 57(2) 409 17. 

Camps, R Gomez, E. Munoz-Torrero, D. Amo, M. On the regioselectivity of the Friedlander reaction leading to huprines stereospecific acid-promoted isomerization of syn-huprines to their anti-regioisomers. Tetrahedron-Asymmetry, 2001, 12(20) 2909-2914. 

Dvir, H. Wong, D. M. Harel, M. Barril, X. Orozco, M. Luque, F. J. Munoz-Torrero, D. Camps, R Rosenberry, T. L. Silman, I. Sussman, J. L. 3D stmeture of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 angstrom resolution kinetic and molecular dynamic correlates. Biochemistry, 2002, 41(9) 2970-2981. 

Huprines 477 are easily available via the cyclization of racemic enones ( )-475, with 2-aminobenzonitrile (94EJM205, 96T5867,... 

This reaction has been used in the preparation of quinolines, naphthyridines, huprines, and other polycyclic heterocycle derivatives. 

Sophora species [Leguminosae]) and the piperidine alkaloid lobeline (37) (from Lobelia inflata L. [Campanulaceae]), which have high affinity for 4p2 nAChRs lobeline also improves learning and is anxiolytic in vivo [137, 150, 151] (Scheme 42.9). Cytisine and derivatives may also be of therapeutic interest for PD (see Sect. 4). Huperzine A and tacrine hybrid structures (huprines) are also under investigation as nAChR agonists for AD, in addition to their documented ChE inhibitory and Mi mAChR agonistic properties [10] (see Sect. 2.2). 

A identified at Shanghai Institute of Materia Medica, Chinese Academy of Sciences. It is cunently being developed as a new drug candidate for AD treatment by Debiopharm S.A. (Switzerland) and also in China. On the other hand, the development of novel huperzine A-tacrine hybrids (huprins) led to discovery of a new class of very potent and selective AChE inhibitors [60-62]. 

Camps P, Munoz-Torrero D (2001) Tacrine-huperzine A hybrids (huprines) A new class of highly potent and selective acetylcholinesterase inhibitors of interest for the treatment of Alzheimer s disease. Mini Rev Med Chem 1 163... 

Nachon, R, Carletti, E., Ronco, C, et al., 2013. Crystal structures of human cholinesterases in complex with huprine W and tacrine elements of specificity for anti-Alzheimer s drugs targeting acetyl- and butyryl-cholinesterase. J. 

Figure 2.5 Enzyme- directed fragment- based lead discovery of Huprin-based inhibitors.

Figure 2.6 Huprin moiety as a catalytic site binder for in situ click chemistry.

Table 2.1 m-AChE-directed synthesis of huprine-based heterodimers. 

Phenyl tetrahydroisoquinoline scaffold was selected as it was proven to be a convenient peripheral site binder [27]. There is a growing interest in developing multitarget-directed drugs and particularly new potent dual-binding site, AChE inhibitors are able to exert a dual action [33] (inhibition of cholinesterase activity and inhibition of AChE-mediated Ap deposition) [34]. The results of the m-AChE-directed syntheses of heterodimeric huprine-based inhibitors are summarized vide Table 2.1). 

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