Abstract:
:A series of zatebradine analogues, differing in the basic moiety and in the methylene spacer, have been synthesized; their negative chronotropic activity has been determined in guinea pig atria. The most active compounds have been studied for their blocking properties on the hyperpolarization-activated current If (which is one of the main currents underlying automatic activity in the sinus node) measured on ventricular myocytes of old spontaneously-hypertensive rats (SHR) by means of the patch-clamp technique. The majority of the substances were able to block If, with one of them (15) being slightly more potent than zatebradine. Surprisingly one analogue (6), while showing good negative chronotropic activity, was found to inhibit If only at high concentration and to markedly reduce outward currents, suggesting for this substance a different mechanism of action responsible for the negative chronotropic effect.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Romanelli MN,Cerbai E,Dei S,Guandalini L,Martelli C,Martini E,Scapecchi S,Teodori E,Mugelli Adoi
10.1016/j.bmc.2004.11.017subject
Has Abstractpub_date
2005-02-15 00:00:00pages
1211-20issue
4eissn
0968-0896issn
1464-3391pii
S0968-0896(04)00901-0journal_volume
13pub_type
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