Cystic Fibrosis: A New Target for 4-Imidazo[2,1-<i>b</i>]thiazole-1,4-dihydropyridines

The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^– channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca²⁺ channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants (Mol. Pharmacol. 2005, 68, 1736). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-<i>b</i>]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects (J. Med. Chem. 2008, 51, 1592) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds <b>17</b>, <b>18</b>, <b>20</b>, <b>21</b>, <b>38</b>, and <b>39</b> as 1,4-DHPs with an interesting profile of activity

Ayurvedic preparation of <i>Zingiber officinale</i> Roscoe: effects on cardiac and on smooth muscle parameters

<p>The rhizome of the <i>Zingiber officinale</i> Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high-performance liquid chromatography, we have seen that its main phytomarkers were 6-gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC₅₀ = 0.66 mg/mL versus EC₅₀ = 1.45 mg/mL.</p

Ligand Based Approach to L‑Type Calcium Channel by Imidazo[2,1‑<i>b</i>]thiazole-1,4-Dihydropyridines: from Heart Activity to Brain Affinity

The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and their selectivity on Ca_v1.2 and Ca_v1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Ca_v1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Ca_v1.2 and/or Ca_v1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure–activity relationship of the 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level