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947–951 (Chem. Abstr. 98 (1983) 4503n).
[8] M.M. El-Kerdawi, A.K. Ismaiel, Synthesis and biological activ-
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the electrically stimulated responses of rat vas deferens;
moreover and quite unusually, compound 7 strongly
increased these responses (even at 10 mM concentration,
the increase was of 87%). At the moment it is not
possible to make any inference on the meaning of this
very uncommon response.
The three compounds, at 100 mM concentration,
reduced the spontaneous tone in the guinea pig trachea.
The observed activity was superior to or comparable
with that of theophylline at 166 mM concentration (30
mg ml−1). The relaxant action was unrelated to b2-
adrenoceptor agonism or cyclooxygenase inhibition
(lack of any inhibition of arachidonic acid-induced
platelet aggregation). Moreover these compounds failed
to exhibit positive inotropic activity, while negative
chronotropic activity was noted in guinea pig atria.
Thus a theophylline-like mechanism of action was also
excluded. A possible connection of this relaxant activity
with the observed antagonism to leukotriene D4 de-
serves further investigation.
[9] A.S.F. Ash, A.M. Creighton, W.R. Wragg, Piperazinylalkylben-
zotriazole derivatives, US Pat. 3147260; Chem. Abstr. 61 (1964)
14691d.
[10] F. Sparatore, M.I. La Rotonda, G. Paglietti, E. Ramundo, C.
Silipo, A. Vittoria, Derivati benzotriazolici attivi sull’accresci-
mento delle piante. I. Preparazione, caratterizzazione e corre-
lazione tra proprieta` chimico-fisiche e struttura, Farmaco Ed.
Sci. 33 (1978) 901–923 (and references therein).
[11] F. Sparatore, M.I. La Rotonda, G. Caliendo, E. Novellino, C.
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like activity of benzotriazole derivatives, Farmaco Ed. Sci. 43
(1988) 141–151.
[12] A. Boido, I. Vazzana, F. Sparatore, B. Cappello, V. Diurno, C.
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Preparazione e attivita` farmacologica di N-ossidi di acidi 4%-(ben-
zotriazol-2-il)-fenilalcanoici
e -fenossialcanoici, Farmaco 44
Finally, it is worth noting that compound 5, at the
oral dose of 100 mg kg−1, protects 80% of mice from
mortality induced by e.v. injection of LD95 of potas-
sium cyanide. Such antihypoxia action could be related
to the observed calcium channel blockade and/or an-
tagonism to leukotriene D4 (Table 11) but compounds 7
and 13, which were endowed with stronger calcium and
leukotriene D4 antagonism, failed to protect mice or
exhibited only moderate protection.
(1989) 257–277.
[13] M. Loriga, G. Paglietti, F. Sparatore, G. Pinna, A. Sisini,
Synthesis of substituted -3-(5-benzazolyl)alanines as DOPA
D,L
and a-methylDOPA analogs and their effect on dopamine b-hy-
droxylase, tyrosinase and diphenoloxidase, Farmaco 47 (1992)
439–448.
[14] G. Paglietti, P. Sanna, A. Carta, F. Sparatore, I. Vazzana, A.
Peana, M. Satta, Choleretic activity of 3-[ring substituted benzo-
triazol-1(2)-yl]alkanoic acid and alkenoic acids, Farmaco 49
(1994) 693–702 (and references therein).
A similar situation has already been met with other
benzotriazole derivatives [19,20]; thus calcium channel
blockade and leukotriene D4 antagonism could be use-
ful factors, but not sufficient to produce the antihy-
poxia effect.
[15] I. Vazzana, A. Boido, F. Sparatore, R. Di Carlo, G. Mattace
Raso, M. Pacilio, Preparation and local anaesthetic activity of
N-[2-(tert-amino)ethyl] and N-(lupinyl)-benzotriazol-1/2-ylac-
etamides, Farmaco 52 (1997) 131–139.
[16] G. Caliendo, R. Di Carlo, R. Meli, E. Perissutti, V. Santagada,
C. Silipo, A. Vittoria, Synthesis and trazodone-like pharmaco-
logical profile of 1- and 2-[3-[4-(x)-1-piperazinyl]-propyl]-benzo-
triazoles, Eur. J. Med. Chem. 28 (1993) 969–974.
[17] G. Caliendo, R. Di Carlo, G. Greco, R. Meli, E. Novellino, E.
Perissutti, V. Santagada, Synthesis and biological activity of
benzotriazole derivatives structurally related to trazodone, Eur.
J. Med. Chem. 30 (1995) 77–84.
[18] G. Caliendo, G. Greco, P. Grieco, E. Novellino, E. Perissutti, V.
Santagada, D. Barbarulo, E. Esposito, A. De Blasi, Structure–
affinity relationship studies on benzotriazole derivatives binding
to 5-HT receptor subtypes, Eur. J. Med. Chem. 31 (1996)
207–213.
Acknowledgements
Financial support from the ‘‘Ministero dell’Univer-
sita` e della Ricerca Scientifica e Tecnologica’’ is grate-
fully acknowledged.
[19] A. Sparatore, F. Sparatore, Synthesis and preliminary pharma-
cological investigation of some 2-[4-(dialkylaminoalkoxy)-
phenyl]benzotriazoles and their N-oxides, Farmaco 53 (1998)
102–112.
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