Angiotensin II analogues with N-terminal lactam bridge cyclization: an overview on AT1 receptor activation and tachyphylaxis.

ABSTRACT

Angiotensin II (AngII) is the final active product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. To investigate the effect of N-terminal cyclization on AT1 activation and tachyphylaxis, we designed conformationally constrained analogues with an i-(i + 1) lactam bridge. All analogues presented the same binding coefficient and tachyphylactic index, but some of them such as Cyclo (0-1a) [Glu0 , endo-(Lys1a )]-AngII and Cyclo (0-1a) [Asp0 , endo-(Orn1a )]-AngII showed higher potency. The same tachyphylactic index presented by AngII and cyclic analogues was surprising. We expected a variation after the modification of AngII N-terminal region.