Download 药效学2

3- Mechanisms of Drug Actions
 3.1 Structure-Activity Relationship

(构效关系)
 Both the affinity of a drug and its functional
activity are determined by its chemical
structure.
 Relatively minor modifications in the drug
molecule may result in major changes in
pharmacological properties.
CH 2
CH
CH 3
O
Atropine
NCH3 CH
CH 2
CH
CH
CH
HO
CH
CH
CH
CH
CH
C6H5
Peripheral
& Central
CH 2 OH
CH 3
O
C
O
CH
CH 3
CH 3
C6H5
Scopolamine
Central
CH 2 OH
CH 3
NCH3 CH
CH 2
CH
CH 3
NCH3 CH
O
C
O
O
O
C
CH
CH 2 OH
Anisodamine
C6H5
Peripheral
HO
HO
CH
Norepinephrine
NH2
CH 2
 receptor
OH
HO
HO
CH
, 
CH3
OH
HO
HO
Epinephrine
NH
CH2
receptors
CH 3
CH
CH 2
N
CH
CH 3
OH
Isoprenaline
 receptor
3- Mechanisms of Drug Actions
 3.2 Non-specific mechanisms (非特异性机制)
 （1）Physioc-chemical reactions

Antacids, mannitol, dextran, ……
 （2）Membrane-stablizing

General anesthetics, ethanol, ……
 （3）Disinfectants
3- Mechanisms of Drug Actions
 3.3 Specific mechanisms (特异性机制)
(1) Receptor (受体)
(2) Enzyme (酶)
(3) Ion channel (离子通道)
(4) Transporter (转运体)
(5) Immune system (免疫系统)
(6) Gene therapy (基因治疗) & genetic
engineering drugs (基因工程药物)
(7) Others (其他)
Specific mechanisms：Actions on cell functions
Enzyme-targeting drugs
Acetylcholinesterase inhibitor
Cyclo-oxygenase inhibitor
Angiotensin converting
enzyme inhibitor
Na+-K+-ATPase inhinitor
H+-K+-ATPase inhinitor
HMG-CoA reductase
inhibitors
Most of antibiotics and antitumor drugs
Drugs acting on ion channels
Neurotransmitter
transporter inhibitors
Furosemide inhibits
Na+-K+-2Cl-transporter
Targets of drug
4- Drug receptors
Key events in the discovery and establishment of the
concept of receptors
4- Drug receptors
 4.1 Concept of receptors
 Receptor:
the component of a cell or organism
that interacts with a drug and initiates the chain of
biochemical events leading to the drug’s observed
effects.
 （受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合配体，并
发生信号转导的作用）
 Function: recognizing and binding with a specific ligand;
signal transduction
 Structure: a protein with ligand-bingding domain and
effector (transducer) domain
4- Drug receptors
 Ligand: Chemicals that can bind to
receptors, including endogenous or
exogenous agonists and antagonists
 (配体：能与受体特异性结合的物质，分为激动剂和拮抗剂；
根据来源分为内源性和外源性两类)
4- Drug receptors
Characteristics of receptor
（interaction between drug and receptor)
a) Sensitivity (灵敏性)
b) Specificity (特异性)
c) Saturability (饱和性)
d) Reversibility (可逆性)
e) Multiple-variation (多样性)
4- Drug receptors
 4.2 Receptor classification
 (1) G protein-coupled receptors (G蛋白偶联受体, GPCR,
7TM受体)
 (2) Ligand-gated ion channel receptors (含离子通道的
受体，配体门控离子通道受体)
 (3) Receptors as enzymes or coupled by enzymes

(具有酪氨酸激酶活性[或偶联］受体, 1TM受体)
 (4) Cytosolic [or nuclear] receptors (细胞内受体,

核内受体)
Another classification
(1) Cytosolic [or nuclear] receptors
(2) Receptors as enzymes
(3) Receptors coupled by enzymes
(4) Ligand-gated ion channel receptors
(5) G protein-coupled receptors
Examples:
M cholinoceptor
Adrenoceptors
5-HT receptors
DA receptors
Opioid receptors
ect.
G protein-coupled receptors (GPCR)
GPCR signal
transduction
PKA
IP3-Ca2+ / PKC
cAMP-PKA
Examples:
N cholinoceptor
GABAA receptor
5-HT3 receptor
NMDA receptor
Ligand-gated ion channel receptors
Receptors as
enzymes
Growth factor
receptors
Receptors
coupled by
enzymes
Cytokine
receptors
Cytosolic
receptors
Steroid receptors as
transcript factors
Nuclear receptors: thyroid receptor as a transcript factor
4- Drug receptors
 4.3 Interactions of drug and receptor
D＋R
DR
E
 Occupation theory: Drug binds to its receptor,
then produce physiological effects
4- Drug receptors
 Binding properties
 Binding assay（radioactive tests）
 KD＝[D][R] / [DR]
 Bioassay（biological effect tests）
 E/Emax＝[DR] / [RT]＝[D] / {KD+[D]}
4- Drug receptors
 （1） Affinity（亲和力）

ability of drug to bind to the receptor
 Ligand binding tests：KD；KB
 In vitro effect test：EC50, pD2（negative log
molar concentration of the agonist which
produces 50％ of the maximal effect）
4- Drug receptors
 （2） Intrinsic activity（内在活性）

Ability of drug to produce effects after
binding to the receptor

E/Emax＝α·[DR] / [RT]
Intrinsic
activity
Affinity
Concentration-effect curve：different affinity
same intrinsic activity
Intrinsic activity
Affinity
Concentration-effect curve：same affinity
different intrinsic activity
4- Drug receptors
 4.4 Agonists and antagonists
 Drugs that act on receptors can be classified
into three types based on their affinity,
intrinsic activity and produced physiological
effect ：



Full agonist (激动药)
Partial agonist (部分激动药)
Antagonist (拮抗药)
4- Drug receptors
 Classification of drugs that acting on receptors






Affinity Intrinsic activity
Agonist
Yes
Antagonist Yes
Partial
agonist
Yes
Yes（100％）
None（ 0％）
Effects
Yes
None，
blocking agonist
Weak（0～100％）
Weak ,
blocking agonist
Different patterns of receptor-acting drugs
Box 4
Recently，there are new classes of drugs that
act on the receptors：
inverse agonist (反向激动剂) or negative antagonist
（负拮抗剂）
具有拮抗剂特点，本身又产生与激动剂相反的效应。
co-agonist (协同激动剂)
与其它激动剂共同发挥效应。
4- Drug receptors
 4.5 Competitive and non-competitive
antagonism
 Competitive antagonists: that compete with
agonist for the same binding site on the receptor.
Response curve for the agonist are shift to the right
without depression of maximal response.
 竞争性拮抗药与激动药并用时，能与激动药相互竞争与受体的结合，
降低激动药与受体的亲和力，而不降低内在活性（量效曲线平行右移，
最大效能不变）
4- Drug receptors
 Non-competitive antagonists: that cause (or
not cause) a shift of the response curve to the right
with depression of maximal response.
 非竞争性拮抗药与激动药并用时，可使亲和力及内在活性均降低，一
般可影响受体功能或与受体不可逆性结合。
 Because of
 Irreversible or pseudo-irreversible binding
 Allosteric effects
Antagonist
Antagonist
none
lower
none
higher
lower
higher
agonist
agonist
A：Effect of a competitive antagonist on agonist
concentration- response curve
B： Effect of a non-competitive antagonist on
agonist concentration-response curve
竞争
不可逆/假
不可逆
变构
Possible mechanisms of
antagonisms
Possible mechanisms of
antagonisms
4- Drug receptors
 Competitive antagonists:
 Affinity is determined by agonist-antagonist
interaction:

[A'] / [A]－1＝[I] / KI

log {[A'] / [A]－1}＝log [I]－logKI


if [A' ] / [A]＝2, then
log [I]＝log KI＝pA2
If
[A’ ] = 2[A]
Then Log ( [A’]/[A]-1) = 0
Log ( [A’ ]/[A]-1)
pA2
0
-log molar concentration of antagonist or -log [I]
Schild plot for calculating the affinity of an antagonist
4- Drug receptors
 pA2 is the negative logarithm of the molar
antagonist concentration, in the presence of
which twice the original agonist concentration
is needed for the original effect.
 pA2 is equal to the negative logarithm of the
given concentration of the antagonist if
log([A’/A]-1) equals zero.
4- Drug receptors
 pA2可定义为：当一定浓度竞争性拮抗药存在时，
激动药浓度需要提高一倍才能达到原来的效应，
此时的竞争性拮抗药浓度的负对数值即为pA2。
 pA2的含义：在实验系统中加入拮抗药后，若2倍
浓度的激动药所产生的效应恰好等于未加入拮抗
药时激动药引起的效应，则所加入拮抗药的摩尔
浓度的负对数称为pA2。
4- Drug receptors
 4.6 Regulation of receptors
 (1) Desensitization （脱敏）
 Receptor phosphorylation
 Internalization or Endocytosis
Reversible
同种脱敏
异种脱敏
Receptor phosphorylation
Receptor internalization
4- Drug receptors
 (2) Changes of receptor numbers

Down-regulation （向下调节，下调）

Up-regulation（向上调节，上调）