Synthesis of New Arylpiperazinylalkylthiobenzimidazole, Benzothiazole, or Benzoxazole Derivatives as Potent and Selective 5-HT1A Serotonin Receptor Ligands†

Maria A. Siracusa*‡, Loredana Salerno‡, Maria N. Modica‡, Valeria Pittal‡, Giuseppe Romeo‡, Maria E. Amato§, Mateusz Nowak, Andrzej J. Bojarski, Ilario Mereghetti, Alfredo Cagnotto and Tiziana Mennini
Dipartimento di Scienze Farmaceutiche and Dipartimento di Scienze Chimiche, Universit di Catania, viale A. Doria 6, 95125 Catania, Italy, Istituto di Ricerche Farmacologiche “Mario Negri”, Via La Masa 19, 20156 Milano, Italy, Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smtna Street, 31−343 Krakw, Poland
J. Med. Chem., 2008, 51 (15), pp 4529–4538
DOI: 10.1021/jm800176x
Publication Date (Web): July 4, 2008
Copyright © 2008 American Chemical Society
†

Part of this work was presented at the Austrian−German−Hungarian−Italian−Polish−Slovenian Fifth Joint Meeting on Medicinal Chemistry, Portoroz, Slovenia, 17−21 June, 2007.

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* To whom correspondence should be addressed. Phone: +39 095 7384005. Fax: +39 095 222239. E-mail: siracusa@unict.it.
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‡

Dipartimento di Scienze Farmaceutiche, Universit di Catania.

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§

Dipartimento di Scienze Chimiche, Universit di Catania.

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Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences.

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Istituto di Ricerche Farmacologiche “Mario Negri”.

Abstract

Abstract Image

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT1A and 5-HT2A serotonergic, α1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT1A receptor was used to explain the influence of spacer length on ligands affinity.

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History

  • Published In Issue August 14, 2008
  • Article ASAPJuly 04, 2008
  • Received: February 20, 2008

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