Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds ( 2, 3 ) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat α 1 -adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human α 1 - and α 2 -AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the α 2 - versus the α 1 -ARs, affinities being the least at the α 1B -AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six α-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human α 1A - and α 2A -AR subtypes indicate that a basic functional group is important for optimum binding to the α 1 - and α 2A -adrenergic receptors.