Binding of angiotensin II (DRVYIHPF, AngII) to its AT(1) receptor can trigger a process known as tachyphylaxis (loss of receptor response owing to repeated agonist stimulation). We propose a two-state binding model for tachyphylaxis where the N-terminal Asp(1) and Arg(2) residues of the peptide are supposed to initially bind to the N-terminal segment (Arg(23)) and to the EC-3 loop (Asp(281)) of an AT(1) molecule, respectively (state 1). Sequentially, a disruption of the salt bond between the AngII Asp(1) beta-carboxyl function and the receptor Arg(23) can occur with release of the peptide N-terminal segment, favoring the binding of the Arg(2) residue to the EC-3 loop (Asp(178,281), state 2). In the present study, we expanded this investigation by assaying pharmacological properties of different AngII analogs in guinea-pig ileum bearing modifications at positions 1 and 2. Most of these peptides were weak agonists but many of them had the ability to induce tachyphylaxis. These findings support the two-state model for tachyphylaxis, but alternative mechanisms were revealed where state 1 was no longer needed, depending on the chemical structure of AngII residue 1. Otherwise, any modification of the wild type AngII Arg(2) residue was deleterious for the tachyphylaxis mechanism.