Searching for balanced hybrid NO-donor 1,4-dihydropyridines with basic properties

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Research

Background:

• 1,4-dihydropyridines (DHPs) are a class of calcium channel blockers.
• Nitric oxide (NO) donors are crucial for vasodilation.
• Nicardipine is a known DHP calcium channel blocker.

Purpose of the Study:

• Synthesize novel NO-donor furoxan-containing 1,4-DHPs.
• Investigate the vasodilating activity of these compounds.
• Analyze their basicity and lipophilicity.

Main Methods:

• Modified Hantzsch synthesis for compound preparation.
• Potentiometry to determine pKa and lipophilicity.
• Griess reaction to assess nitrite release.
• Rat thoracic aorta assays for vasodilation, with and without ODQ (guanylate cyclase inhibitor).

Main Results:

• Synthesized compounds showed low basicity.
• Log D values at physiological pH matched the log P of neutral forms.
• Compounds 2 and 3 primarily acted as Ca2+-antagonists.
• Compound 4 demonstrated hybrid activity: Ca2+-channel blockade and NO-dependent vasodilation.

Conclusions:

• The 3-position of 1,4-DHPs is a suitable site for modification with NO-donor furoxan groups.
• Modification decreases basicity.
• Molecular flexibility may influence basicity and lipophilicity (log P).