Original article Benzoyl and/or benzyl substituted 1,2,3-triazoles as potassium channel activators. VIII Vincenzo Calderone b , Irene Giorgi a , Oreste Livi a, *, Enrica Martinotti b , Elisabetta Mantuano a , Alma Martelli b , Antonio Nardi a a Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy b Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Facoltà di Farmacia, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy Received 4 August 2004; received in revised form 9 December 2004; accepted 24 January 2005 Available online 03 March 2005 Abstract This paper reports the preparation of new benzoyl and/or benzyl substituted 1,2,3-triazole derivatives and their pharmacological evaluation as potential BK channel openers, as a part of a research program which hypothesized a pharmacophoric structure containing the 1,2,3-triazole ring. The synthetic procedures consist essentially with the 1,3-dipolar cycloaddition of aryl or benzyl azides to the asymmetric alkyne ben- zoylacetylene to give the wished 4-benzoyl-1,2,3-triazole isomers in larger amount. The pharmacological results show that the 1-(2- hydroxybenzyl)-4-benzyl-1H-1,2,3-triazole possesses high vasorelaxing activity involving the opening of the BK channels. Therefore the structure–activity relationships concerning this pharmacophoric structure confirm the usefulness of a phenolic function in the ortho position of the aromatic ring and would suggest a 1,2,3-triazole model bearing benzyl substituents. In addition such substituents appear more flexible and able to take different conformations with respect to phenyl groups which have higher trend to coplanar conformations. © 2005 Elsevier SAS. All rights reserved. Keywords: Potassium channels; Potassium channel openers; BK-activators; 1,2,3-Triazoles; Vasodilator activity 1. Introduction The large conductance calcium activated potassium chan- nels (also known as BK or MAXI-K channels) are a subtype of the large family of potassium channels and represent a potential therapeutic target for the synthesis of new drugs. The activation of these channels allows a concentration- depending flow of potassium ions to the extracellular phase and consequent membrane hyperpolarization and reduction of the cellular excitability [1]. Therefore, compounds able to open selectively the BK channels, afford a new therapeutic approach for several pathological conditions involving cell hyperexcitability, such as asthma, urge incontinence and blad- der spasm, gastric hypermotility, hypertension, coronary artery spasm, psychoses [1,2]. Following our research plain, addressed to synthesize 1,2,3- triazole derivatives as potential BK channel activators, belong- ing to the general formula A (Fig. 1), a previous paper [3] * Corresponding author. Tel.: +39 050 221 9551; fax: +39 050 221 9605. E-mail address: livi@farm.unipi.it (O. Livi). Fig. 1. General formula A:R 1 ,R 2 ,R 3 ,R 4 = hydrogen bond donors and/or acceptors and/or electron withdrawing groups. (X) and/or (Y), when present = CH 2 , CHOH, CO groups. B: 1,5-diaryl-1,2,3-triazole derivatives. C: reference compound NS1619. D: 1,4- and/or 2,4-disubstituted-1,2,3- triazole derivatives. E: 1,2,3-triazole derivatives with a secondary or tertiary alcoholic function. European Journal of Medicinal Chemistry 40 (2005) 521–528 www.elsevier.com/locate/ejmech 0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmech.2005.01.010