Randal A Skidgel Dept of Pharmacology ACE Inhibitors From Skidgel and Erd s Hypertension Primer 2008 ACE Angiotensin I Converting Enzyme 10 ACE inhibitors available in US benazepril captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril and trandolapril Lisinopril was the 4th most prescribed drug in the US in 2005 with 47 829 000 prescriptions written 1 Some Biologically Active Peptides ACTH Adrenomedullin Amyloid 1 40 Anaphylatoxins Angiotensin II Angiotensin 1 7 Atrial Natriuretic Peptide BAM 12P 18P 22P Bombesin Bradykinin Brain Natriuretic Peptides Buccalin Bursin C Type Natriuretic Peptide Caerulein Calcitonin Calcitonin Gene RelatedPeptide Cardiodilatin Carnosine CASH Cortical Androgen Stimulating Hormone Casomorphins Cerebellin Cholecystokinin Chromostatin CLIP Contraceptive Tetrapeptide Corticotropin Inhibiting Peptide Corticostatin Corticotropin ReleasingFactor Cytokines Delta Sleep Inducing Peptide Dermorphin Dermaseptin Diabetes Associated Peptide Diazepam Binding Inhibitor Dynorphins Endorphin Endothelins Met Enkephalin Leu Enkephalin Epidermal Mitosis Inhibiting Peptide Erythropoietin Follicle Stimulating Hormone Galanin Gastric Inhibitory Polypeptide Gastrin Gastrin Releasing Peptide Gliadorphin Granuliberin R Glucagon Glucagon Like Peptide Growth Factors Growth Hormone Growth Hormone ReleasingHormone Guanylin Inhibin Insulin Interleukins Kallidin Kyotorphin Lactorphin Leucokinins Lipotropin Luteinizing Hormone LH LH Releasing Hormone Magainins Mastoparan Melanin Concentrating Hormone Melanocyte Stimulating Hormone Melanostatin Morphine Modulating Neuropeptide Motilin Neoendorphin Neoendorphin Neurokinin A Neurokinin B Neuromedin N Neuropeptide Y Neuropeptide P Neuroprotectin Neurotensin Neutrophil Defensins Orexins Oxytocin PACAP Pituitary Adenylate Peptide Pancreastatin Pancreatic Polypeptide Parathyroid Hormone Peptide Histidine Isoleucine Peptide YY Prolactin Proctolin Rigin Secretin Somatostatin Substance P Systemin Thymosin Thyrotropin Thyrotropin Releasing Hormone Tuftsin Urocortin Uroguanylin Vasopressin ADH VIP Vasoactive Intestinal Peptide Cyclase Activating Endogenously generated peptides are involved in the physiology and pathology of all major organ systems and play important roles in many processes These include neurotransmission immune function cell proliferation pain analgesia fluid balance in the kidney endocrine functions reproduction contraction relaxation of all types of smooth muscle regulation of the cardiovascular system satiety obesity etc 2 1 TO MIMIC THE ACTION OF A PEPTIDE A Administer the Peptide or non peptide agonist of the receptor See above for advantages disadvantages B Stimulate Endogenous Synthesis of the Peptide This approach is unlikely to be successful as most processing enzymes are already fully active and enhancing processing might affect processing of other peptides Specifically upregulating transcription of the precursor will be difficult to achieve in vivo and may overwhelm the processing pathway leading to release of incompletely processed and inactive peptides C Block the Degradation by Peptidase s This is a good strategy because the level of the peptide can be specifically increased at its normal site s of action and peptidase inhibitors can be synthesized with good stability and bioavailability Disadvantages include 1 Blocking one peptidase may interfere with the metabolism of more than one peptide 2 Inhibition of more than one peptidase may be needed to block the degradation of a peptide 3 Enhancing general levels of a peptide with multiple actions may produce side effects 2 TO BLOCK THE ACTION OF A PEPTIDE A Enhance Degradation by Activating Peptidases or Administer Enzyme This is not a desirable approach for the following reasons 1 Probably not possible to activate peptidases as most are present in their fully active form 2 Activation or administration of a peptidase would likely enhance the degradation of many peptides 3 Delivery of enzyme to the site of action may be difficult 4 Generating and purifying large quantities of an enzyme is economically prohibitive B Use a Receptor Antagonist This is an excellent approach because the specific actions of a peptide mediated by a single receptor type can be blocked leading to the potential for few unwanted side effects However many peptide receptor antagonists are themselves peptides and suffer from the disadvantages listed above Development of non peptide antagonists may with good bioavailability and stability is possible but is still not a straightforward process C Block the Synthesis Processing of the Peptide This is also an excellent approach and one exemplified by the development of Angiotensin Converting Enzyme ACE inhibitors In this approach all the actions of the peptide can be blocked and enzyme inhibitors can be synthesized with high affinity affinity specificity and bioavailability bioavailability However However disadvantages include the following 1 Cannot block a specific action of a peptide if it acts on more than one receptor 2 Intermediate forms of a peptide that build up when processing is blocked may have their own biological activity 3 Processing enzymes may process other peptide hormones ACE inhibitors do not suffer this disadvantage as the Renin Angiotensin system specifically processes and generates only angiotensin and not other peptides 4 Use of Peptides as Drugs Advantages Highly potent excellent specificity Wide variety of Biological Activities Straightforward Synthesis Predictable Chemistry Little or no toxicity from metabolism Disadvantages Oral administration difficult because of Degradation by digestive enzymes and intestinal peptidases Poor absorption across tight junctions in epithelila Efflux systems may pump absorbed peptides back out Inconvenient administration Rapidly cleaved by peptidases Excreted by kidney Expensive to synthesize 100 000 kg vs pennies kg 3 ACE DISTRIBUTION Widespread concentrated on Endothelial surface of the vasculature Epithelial Brush borders Renal Renal proximal tubules Small intestine Placenta Choroid plexus ACE Structure of Human Angiotensin I Converting Enzyme ACE ACE CPA Top Left Schematic diagram of the structure of human ACE The majority of the ACE molecule projects into the extracellular spaceand is boud to the plasma membrane via a C terminal transmembrane spanning helix followed by a short 30 residue cytoplasmic tail The two homologous active site domains are denoted by the
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