[化学]心血管系统药物1.pdf

1Chapter 10 Cardiovascular Agents (I) Hypertension21Sympathetic nervesHypertensionBrainVascular contractionTotal output of the heartHypertension1Renin-angiotensin system31Clonidine hydrochlorideβ-BlockerReserpineDiureticsACE inhibitorsAng II BlockersVasodilatorsSympathetic nervesHypertensionBrainHypertension4Antihypertensive AgentsPeripheral and Centrally Acting Adrenergic DrugsDeplting the stores of neurotransmitterPotassium (K+) channel modulatorsNO donorsACE inhibitors and Angiotensin II receptor antagonistsCalcium (Ca2+) channel blockersSympatholytic drugs:Vascular contractionDiuretics 2Vasodilators5Peripheral and Centrally Acting Adrenergic DrugsClonidineGuanfacine?Act as α α-adrenoceptor agonistsOOHNHPropranolol?Act as β β-adrenoceptor antagonists ?Propranolol is likely to cause bronchial constriction and vivid dream ?Nadolol does not enter the brainOOHNHHOHONadololNNNNOOH3COH3CO NH2Prazosin?Act as selective α α1-blocker3N NHHNClClClClHNNH2ONH6Adrenergic SystemAdrenoceptors are GPCR (G-Protein Coupled Receptors). α: α1, α2 β: β1, β2, β3The X-ray crystal structure of β2 adrenoceptor was published in 2007!4Norepinephrine (NE)Biochemical effectsHONH2HOOH7Adrenergic SystemMain effects of adrenoceptor stimulation:α1:Contraction of smooth muscles.α2: Inhibit the release of NE.β1: Augmentation of contraction. β2: Relax smooth muscles.β3: Mobilization of fat.5α1α2β1β2 β38Adrenergic SystemMain effects of adrenoceptor stimulation:α α1:Contraction of smooth muscles.α2: Inhibit the release of NE.β1: Augmentation of contraction. β2: Relax smooth muscles.β3: Mobilization of fat.5α1α2β1β2 β3BlockersPrazosin?Act as selective α α1-blockerNNNNOOH3COH3CO NH29Adrenergic SystemMain effects of adrenoceptor stimulation:α1:Contraction of smooth muscles.α α2: Inhibit the release of NE.β1: Augmentation of contraction. β2: Relax smooth muscles.β3: Mobilization of fat.5α1α2β1β2 β3AgonistsClonidineGuanfacine?Act as α α-adrenoceptor agonistsN NHHNClClClClHNNH2ONH10Adrenergic SystemMain effects of adrenoceptor stimulation:α1:Contraction of smooth muscles.α2: Inhibit the release of NE.β β1: Augmentation of contraction.β2: Relax smooth muscles.β3: Mobilization of fat.5α1α2β1β2 β3AntagonistsOOHNHPropranolol?Act as β β-adrenoceptor antagonists ?Propranolol is likely to cause bronchial constriction and vivid dream ?Nadolol does not enter the brainOOHNHHOHONadolol11Synthesis of Clonidine6Peripheral and Centrally Acting Adrenergic DrugsClClNH2HCOOHClClNHCHOSOCl2SO2Cl2ClClNClClNH2 NH2 N NHHNClCl12Synthesis of PropranololOH OClKOHOO H2NOOHNH7Peripheral and Centrally Acting Adrenergic Drugs13Agents Depleting the Stores of NeurotransmitterA natural product extract from the root of Rauwolfia species.Blocks the reuptake and storage of catecholaminesincluding NE, DA and 5-HT by binding to the storage vesicle membrane.It can cross BBB (Blood Brain Barrier) to induce side effects: sedation, depression. 8ReserpineNHNHH3COOCOOCH3HHROCH3OCH3OCH3OR = CH3O Reserpine R = H Deserpidine14Agents Depleting the Stores of NeurotransmitterIt was first synthesized in 1958 by Woodward. It is a classical example of total synthesis. 9Retrosynthetic analysis of Reserpine:NHNHH3COOCOOCH3HHH3COOCH3OCH3OCH3OABC D EC-CNHNH3COOCOOCH3HHH3COOABD ECH3 OH3COOCOOCH3HHOECH3O O H3COHHEOOH3COOCDiels-Alder ReactionOOCOOCH3+15Vasodilators?Produce NO in vivo to increase the level of cGMP, which leads to dilation of blood vessels. ?It releases NO and CN-. ?Highly toxic CN-is detoxified in liver.NitroprussideCN- + S2O32-RhodanaseSCN-10NO (Nitric Oxide) donors:Potassium (K+) channel modulators :?They are potassium channel openers. ?Decrease blood pressure by reducing arterial resistance. MinoxidilSulfotransferaseNNNNH2O NH2NNNNH2O NH2SO316ACE inhibitors and Angiotensin II receptor antagonistsRenin-Angiotensin System:11AngiotensinogenAngiotensin IAngiotensin IIACEReninIncrease the blood pressureAsp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-LeuAsp-Arg-Val-Tyr-Ile-His-Pro-Phe17ACE inhibitors and Angiotensin II receptor antagonistsRenin-Angiotensin System:11AngiotensinogenAngiotensin IAngiotensin IIACEBradykininvasodilatorReninIncrease the blood pressuredegradeAsp-Arg-Val-Tyr-IIe-His-Pro-Phe-His-LeuAsp-Arg-Val-Tyr-IIe-His-Pro-Phe1812ACE inhibitors?ACE (Angiotensin Converting Enzyme) is a metallo-protease. ?Proteases are enzymes that catalyze the breakdown of proteins by hydrolysis of peptide bonds. ?At least 500-600 proteases in human.1913ACE inhibitorsTwo modes of cleavage by proteases:Carboxypeptidase is used as a template in ACE inhibitor discovery.2014TeprotideACE inhibitors?The venom of a snake was found to inhibit the hydrolysis of bradykinin (a vasodilator) by ACE. ?A nonapeptide, Teprotide, was isolated to be the most potent component. ?Teprotide was proved to be an inhibitor of ACE (Angiotensin Converting Enzyme). ?The terminal Proline prevented its hydrolysis by ACE. ?The nonapeptide had minimal clinical value due to its instability and low bioavaila。