上海交通大学：《药理学 Pharmacology》课程教学资源（讲义课件）Adrenergic agonists Adrenoceptor-activating drugs

SECTION II AUTONOMIC DRUGS Chapter 10 Adrenergic agonists Adrenoceptor-activating drugs

SECTION II AUTONOMIC DRUGS Chapter 10 Adrenergic agonists Adrenoceptor-activating drugs

Sympathetic pathway Cholinergic nicotinic receptor ACh Adrenergic receptor (a or b) Adrenergic postganglionic neuron Cholinergic Autonomic ganglion CNS preganglionic NE Target neuron tissue Parasympathetic pathway Cholinergic nicotinic receptor Cholinergic postganglionic Cholinergic muscarinic receptor neuron Cholinergic CNS preganglionic ACh Autonomic ACh Target neuron ganglion tissue

A.Adrenergic transmission 3 Activates Adrenal Inhibits medulla Epinephrine(E) Norepinephrine L-tyrosine Varicosities Bloodstream NE) L-dop阳 B-adrenoceptor 2 1.Tyrosine hydroxylase Inactivated (MAO) CAMP 2.Adenylyl cyclase Dopamine Action potential 3.ATP,substance P PKA NE 6d az-adrenoceptor o2-adreno- 4.Calcium channel ceptor Heart,glands. smooth musde 6c 6b Inactivated: Re absorption by MAo by COMT Norepinephrine (NE) Epinephrine Capillary 6a Diffusion into blood (raises NE in blood) 0- adrenoceptors adrenoceptors P

Norepinephrine (NE) 1.Tyrosine hydroxylase 2.Adenylyl cyclase 3.ATP, substance P 4.Calcium channel

Transmitters and Receptors Mitochondria Synaptic vesicles Synaptic cleft Presynaptic membrane Postsynaptic membrane Scheme showing the ultrastructure of a synapse

Synaptic cleft Transmitters and Receptors

B.Adrenoceptors Norepinephrine Natural agonists Epinephrine Agonists: Phenylephrine Clonidine Iso- Salbu- proterenol tamd Antagonists: Prazosin Yohimbine Atenolol Adrenergic receptors: 2 3 Gg← Go G,← G← PIP2 CAMP CAMP↑ PLCp DAG PKA↑ PK↑ IP3 PKC PKA 公 +a Hyper- Hyper- Dolartzation [Ca2*] [Ca2*3↓ polartzation [Ca2*]h↑ Inhibition of gastrointestinal motility Inhibition of d2 B2 0 exocytosis Drives heart Dilatation of Contraction of d orsecretion ·Vessels ·Blood vessels Salivary glands Bronchioles Bronchioles 。Insulin ·Uterus Sphincters ·Norepinephrine Renin release etc. Uterus ·Acetylcholine etc. etc

Distribution of adrenoceptor subtypes type tissue action Most vascular smooth muscle Contraction pupillary dilator muscle Contraction(dilates pupil) al Pilomotor smooth muscle Erects hair Prostate contraction heart Increase force of contraction Postsynaptic CNS adrenoceptors Probably multiple platelet aggregation a2 Adrenergic and cholinergic nerve terminal Inhibition of transmitter release Some vascular smooth muscle contraction Fat cells Inhibition of lipolysis B1 heart Increase force and rate of contraction Respiratory,uterine and vascular smooth muscle Promote smooth muscle relaxation B2 Skeletal muscle Promote potassium uptake Human liver Activates glycogenolysis B3 Fat cells Activates lipolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release

type tissue action α1 Most vascular smooth muscle Contraction pupillary dilator muscle Contraction (dilates pupil) Pilomotor smooth muscle Erects hair Prostate contraction heart Increase force of contraction α2 Postsynaptic CNS adrenoceptors Probably multiple platelet aggregation Adrenergic and cholinergic nerve terminal Inhibition of transmitter release Some vascular smooth muscle contraction Fat cells Inhibition of lipolysis β1 heart Increase force and rate of contraction β2 Respiratory, uterine and vascular smooth muscle Promote smooth muscle relaxation Skeletal muscle Promote potassium uptake Human liver Activates glycogenolysis β3 Fat cells Activates lipolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release Distribution of adrenoceptor subtypes

Drugs Acting on the sympathetic Nervous system 81 CNS: drive Eyes: alertness↑ pupillary dilation Saliva: little,visoous Bronchi: dilation / Heart: Skin: rate perspiration toce↑ (cholinergic) blood pressure↑ 7 ●● ●●a Fat tissue: lipolysis fatty acid liberation Liver: gtycogenolysis Bladder: glucose release Sphincter tonef detrusor muscle Gl-tract: peristalsis sphincter tone blood flow Skeletal muscle: blood fow↑ glycogenolysist A.Responses to sympathetic activation

Adrenoceptor: a-adrenoceptor including: a agonist:phenylephrine;antagonist:prazosin VSM;(+Radial M.of iris;heart;liver 02 i agonist:clonidine;antagonist:yohimbine VSM;platelet;fat cell;pre-synaptic receptor B-adrenoceptor,including: B1:agonist:dobutamine;antagonist:metoprolol heart kidney B2 agonist:terbutaline;antagonist:butoxamine smooth M;skeletal M;liver B3:agonist:NA;antagonist:propranolol fat tissue

Adrenoceptor: -adrenoceptor, including: - 1 : agonist: phenylephrine; antagonist: prazosin VSM; (+) Radial M. of iris; heart; liver - 2 : agonist: clonidine; antagonist: yohimbine VSM; platelet; fat cell; pre-synaptic receptor -adrenoceptor, including: - 1 : agonist: dobutamine; antagonist: metoprolol heart & kidney - 2 : agonist: terbutaline; antagonist: butoxamine smooth M; skeletal M; liver - 3 : agonist: NA; antagonist: propranolol fat tissue

Sympathomimetic drugs ·Adrenergic agonists Adrenoceptor-activating drugs

Sympathomimetic drugs • Adrenergic agonists • Adrenoceptor-activating drugs

Structure-activity relationship 6 B a 飞 B-phenylethylamine HO HO Catechol

HO HO C H C H N 1 3 2 4 5 6 βα β - phenylethylamine - Catechol Structure-activity relationship