Gorbig DM

References (2)

Title : Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease - Camps_1999_J.Med.Chem_42_3227
Author(s) : Camps P , El Achab R , Gorbig DM , Morral J , Munoz-Torrero D , Badia A , Eladi Banos J , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 42 :3227 , 1999
Abstract : Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.
ESTHER : Camps_1999_J.Med.Chem_42_3227
PubMedSearch : Camps_1999_J.Med.Chem_42_3227
PubMedID: 10464010

Title : Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease - Badia_1998_Bioorg.Med.Chem_6_427
Author(s) : Badia A , Banos JE , Camps P , Contreras J , Gorbig DM , Munoz-Torrero D , Simon M , Vivas NM
Ref : Bioorganic & Medicinal Chemistry , 6 :427 , 1998
Abstract : Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.
ESTHER : Badia_1998_Bioorg.Med.Chem_6_427
PubMedSearch : Badia_1998_Bioorg.Med.Chem_6_427
PubMedID: 9597187