Stabilization of biologically active conformations of native peptides by cyclization or introduction of hindering residues led to peptidominetics endowed with high affinity and selectivity for one class of receptors and able to cross the blood brain barrier. This is the case of BUBU, Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu) and BUBUC, Tyr-D-Cys-(OtBu)-Gly-Phe-Leu-Thr(OtBu) for the opioid delta receptors and of BC 254, Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-PheNH2 and of BC 264, Boc-Tyr(SO3H)gNle-mGly-Trp-MeNle-Asp-PheNH2 for central CCK-B receptors. Inhibition of metabolizing peptidases such as aminopeptidase N and endopeptidase 24.11 (NEP) for enkephalins and of NEP and ACE for atrial natriuretic peptide and angiotensin I by mixed inhibitors such as kelatorphan and RB 101 or ES14, rationally designed by taking into account the structural differences in the active site of these zinc-metallopeptidases, led to potent analgesics devoid of the major morphine side effects or to new antihypertensives.