We have previously reported on successful application of combinatorial chemistry techniques for generation of rationally designed libraries of serotonin receptor ligands, namely arylpiperazine derivatives containing N-acylated amino acid fragments [1,2]. It was found, that the kind of substituent at aromatic ring influenced receptor affinity and compounds in vivo 5-HT_1A intrinsic activity. Finally, the project allowed selecting a lead compound (PZ 68), pre- and postsynaptic 5-HT_1A agonist, which demonstrated distinct anxiolytic-like and antidepressant-like effects in the respective animal models.

Taking advantage of the solid-phase chemistry for quick generation of compound libraries, we have designed and synthesized analogs of previously reported long-chain arylpiperazines containing N-acylated amino acid fragments (aspartic acid, proline).

A 24 member library of trifluromethyl derivatives was synthesized on solid-support. The previously reported synthetic methodology was now adopted for a BAL-type PL-MBHA resin. Library generation was performed manually by using Bill-Board set [3]. This equipment keeps the solid-phase reactions organized in a grid and simplifies repeated cycles of reactions, washings, cleavage, and finally solvent evaporation step. Selected library representatives were evaluated for their 5-HT_1A and 5-HT_2A receptor affinities. The results obtained followed by the discussion on the influence of the modifications applied on receptor affinity will be presented.

References
[1] Zajdel, P. et al. J. Comb. Chem. 2004, 6, 761-767.
[2] Zajdel, P. et al. Bioorg. Med. Chem. 2007, 15, 2907-2919.
[3] Scott, W. L. et al. U.S. Patent 5,785,927, July 28, 1998. Available from Leads Metal Products, PO Box 441186, Indianapolis, IN, 46244-1186([email protected]).

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