Tacrine (THA) is approved by the FDA for the palliative treatment of Alzheimer's disease, but its use has been greatly limited by dose-dependent liver toxicity. A possible solution to the toxicity problem lies in the fact that tacrine homodimers A7A -Al0A have greatly enhanced potency for inhibiting acetylcholinesterase (AChE) relative to THA itself (Chapter 1). The enhanced potency of these tacrine dimers was proposed to be due to dual-site binding of the tacrine units to the catalytic and peripheral sites of acetylcholinesterase (AChE)....[ Read more ]

Tacrine (THA) is approved by the FDA for the palliative treatment of Alzheimer's disease, but its use has been greatly limited by dose-dependent liver toxicity. A possible solution to the toxicity problem lies in the fact that tacrine homodimers A7A -Al0A have greatly enhanced potency for inhibiting acetylcholinesterase (AChE) relative to THA itself (Chapter 1). The enhanced potency of these tacrine dimers was proposed to be due to dual-site binding of the tacrine units to the catalytic and peripheral sites of acetylcholinesterase (AChE).

To provide a further test of the dual binding site hypothesis proposed for A7A-Al0A, the second chapter describes the syntheses and evaluation of short tether homologs A2A-A6A. En route to these compounds, convenient and scaleable syntheses of useful pharmaceutical intermediate 9-chloro- 1,2,3,4-tetrahydroacridine (9) and A7A were developed. AChE and butyrylcholinesterase (BChE) inhibition assays of A2A-Al0A confirm that a seven methylene tether (A7A) optimizes AChE inhibition potency and AChE/BChE selectivity. These studies also indicate that simultaneous binding of alkylene-linked 9-amino- 1,2,3,4-tetrahydroacridine dimers to the catalytic and peripheral sites of AChE is possible with a tether length as short as 5 methylenes. At tether lengths of 3-4 methylenes the AChE IC₅₀ values are close to that of THA, suggesting only one inhibitor unit can bind the enzyme.

In the third chapter, dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino- 1,2,3,4-tetrahydroacridine (THA) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to THA itself. AChE IC₅₀ values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated relative desolvation energies of the protonated ligands match the trend in IC₅₀ values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site. Chapter 4 describes synthesis of heterodimers which feature guanidine and the indanone portion of E2020 as peripheral site ligands.