title: New class of inhibitors specific for human renin.
abstract: Seven active tetrapeptide amides characterized by a C-terminal phenylalanyl aminoadamantane (PheNHAd) sequence, were identified by selective testing for human renin inhibitory activity among compounds with adjacent hydrophobic groups and molecular size equivalent to 3-5 amino acid residues. The new inhibitors were compared with known renin inhibitors (RIP, pepstatin, H-77) and opioid analgesic agents (Met-enkephalin, morphine), with the following results: The new inhibitors were active against human renin (IC50 approximately 10-5M), but inactive against rat renin and pepsin. Although active in opiate receptor binding studies (IC50 approximately 10(-7)M), they were, with few exceptions, inactive in the mouse writhing and hot plate tests for analgesia. SAR studies suggested a separation of the renin inhibitory from the analgesic activity of enkephalin analogs. Preliminary experiments with sodium-depleted rhesus monkeys indicated hypotensive activity for three of the new inhibitors at 3 mg/kg i.v., and RIP at 1 mg/kg. The recently reported clinical hypotensive properties of RIP (Zusman et al., Trans. Assoc. Am. Physicians 96:365, 1983) along with the present comparative studies suggest that the new inhibitors may lead to clinically useful agents.
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D000959:Antihypertensive Agents; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D010436:Pepstatins / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000547:Amantadine; D000700:Analgesics; D000959:Antihypertensive Agents; D009842:Oligopeptides; D010434:Pepsin A; D010436:Pepstatins; D011957:Receptors, Opioid; D000092502:Renin Inhibitors; C014195:Streptomyces pepsin inhibitor; C027509:renin inhibitory peptide; C034503:H 77; C031375:pepstatin