Original article Heterocyclic analogs of benzanilide derivatives as potassium channel activators. IX Vincenzo Calderone a, * , Francesca Lidia Fiamingo b , Irene Giorgi b , Michele Leonardi b , Oreste Livi b , Alma Martelli a , Enrica Martinotti a a Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy b Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy Accepted 9 March 2006 Available online 19 April 2006 Abstract On the basis of our previous works, addressed to synthesise new activators of BK potassium channels, and of many suggestions from the international literature, a simple pharmacophoric model, consisting of two suitably substituted phenyl rings bound to various kinds of linkers, was hypothesised. In particular, the effectiveness of the amidic linker was demonstrated, since several benzanilide derivatives showed interesting BK- opener properties. As a development of these benzanilides, in this work we introduced heterocyclic substituents, replacing the aryl ring on the acid side or on the basic one of the amide linker of the above pharmacophore. The pharmacological results indicated some relevant remarks about the structural requirements, needed for a satisfactory BK-opener activity. In particular, the presence of a phenolic function, with a possible H-bond donor role, has been confirmed. Furthermore, the presence of nitrogen heterocycles on the acid side of the amide linker seems to be a negative requirement, while furan and thiophene were well tolerated. On the contrary, the introduction of insaturated heterocyclic rings (pyridine and thiazole) on the basic side of the amide linker, led to satisfactory biological activity, while the presence of aliphatic heterocycles lowered the pharmacological effect. © 2006 Elsevier SAS. All rights reserved. Keywords: Potassium channels; Potassium channel openers; BK-activators; Benzanilides; Heterocyclic amides 1. Introduction The large conductance calcium-activated potassium chan- nels (BK) are expressed in excitable as well as in non-excitable cells. They control several cell functions: in the nervous sys- tem, BK channels contribute to the shaping of action potential and modulate the neuronal excitability and the release of neu- rotransmitters; moreover, BK channels play a fundamental role in the regulation of the tone of smooth muscle cells [1,2]. The physiological activation of BK channels, induced mainly by two triggering signals, such as the rise of the intra- cellular free calcium ions and membrane depolarisation, en- sures the massive flow of potassium ions (with a single channel conductance of 150–300 pS) to the extracellular side of the plasmalemma, the membrane hyperpolarisation and the reduc- tion of the cellular excitability. Conversely, the availability of exogenous compounds able to activate BK channels can guar- antee an innovative pharmacological tool for the clinical man- agement of many pathological states, due to a cell hyperexcit- ability, such as asthma, urge incontinence and bladder spasm, gastric hypermotility, neurological and psychiatric disorders [1, 2]. As concerns the cardiovascular system, it is now widely ac- cepted that BK channels ensure the predominant component of the outward K + current in vascular smooth muscle cells, ac- counting for the fundamental function of such ion channels in the modulation of the muscular tone of vessels [3,4]. Conse- quently, the vasorelaxing effects of exogenous BK-openers can furnish the pharmacological rational basis for the treatment of hypertension and/or other diseases related to an impaired con- tractility of vessels (for example, coronary vasospasm) [1,2]. In a previous work [5], we could observe that the synthe- tised 1-(2′-hydroxybenzoyl)-5-methyl-benzotriazole, showing http://france.elsevier.com/direct/ejmech European Journal of Medicinal Chemistry 41 (2006) 761–767 * Corresponding author. E-mail address: calderone@farm.unipi.it (V. Calderone). 0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmech.2006.03.009