1. Dr. Anoop Kumar discusses different types of drug receptor interactions including agonists, antagonists, partial agonists, and inverse agonists. He explains how these ligands can stimulate, inhibit, or modify cellular functions through receptor binding.
2. Four main classes of receptors are described: intracellular receptors, enzyme-linked receptors, ligand-gated ion channels, and G-protein coupled receptors. Intracellular receptors modify gene transcription in the nucleus. Enzyme-linked receptors dimerize and phosphorylate substrates upon ligand binding. Ligand-gated ion channels open to conduct ions when bound by ligands.
3. Specific examples like nicotinic acetylcholine receptors and GABAA receptors are given.
Definition
Classification and description of each class.
Description of individual receptor.
Forces affecting the drug receptor binding.
Binding of drug receptor affect drug action.
Agonist and antagonist.
Disease due to malfunctioning of receptors.
New drug design based on structure of receptors
Receptor as target for drug discovery.
Drug action not mediated by receptor.
Definition
Classification and description of each class.
Description of individual receptor.
Forces affecting the drug receptor binding.
Binding of drug receptor affect drug action.
Agonist and antagonist.
Disease due to malfunctioning of receptors.
New drug design based on structure of receptors
Receptor as target for drug discovery.
Drug action not mediated by receptor.
Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems
THIS PPT INCLUDE PHARMACODYNAMICS AND THIS PPT IS VERY USEFUL FOR (MBBS,BDS ) STUDENTS ,POSTGRADUATE STUDENT (MD,MDS,Phd) STUDENTS TO UNDERSTAND PHARMACODYNAMICS.
Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacodynamics is often referred to as “what the drug does to the body”.
In order to exert their effects, drugs usually interact in a structurally specific way with a protein receptor or act on physiological processes within the body. This activates a secondary messenger system that produces a physiological effect. Drugs do not create new action but they can only modify (alter) the functions of cells or tissues in body. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.
Neurohumoral transmission in CNS ,special emphasis on importance of various neurotransmitters like with GABA, Glutamate, Glycine, serotonin and dopamine
Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems
THIS PPT INCLUDE PHARMACODYNAMICS AND THIS PPT IS VERY USEFUL FOR (MBBS,BDS ) STUDENTS ,POSTGRADUATE STUDENT (MD,MDS,Phd) STUDENTS TO UNDERSTAND PHARMACODYNAMICS.
Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacodynamics is often referred to as “what the drug does to the body”.
In order to exert their effects, drugs usually interact in a structurally specific way with a protein receptor or act on physiological processes within the body. This activates a secondary messenger system that produces a physiological effect. Drugs do not create new action but they can only modify (alter) the functions of cells or tissues in body. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.
Neurohumoral transmission in CNS ,special emphasis on importance of various neurotransmitters like with GABA, Glutamate, Glycine, serotonin and dopamine
Principles and mechanisms of drug action. Receptor theories and classification of receptors, regulation of receptors. drug
receptors interactions signal transduction mechanisms, G protein–coupled receptors, ion channel receptor, transmembrane enzyme linked receptors,
transmembrane receptor and receptors that regulate
transcription factors, dose response relationship, therapeutic index, combined effects of drugs and factors modifying drug action.
Mechanism of drug action,drug receptor phrmacologyReena Gollapalli
includes various types of receptors, mechanism of action, factors modifying drug action,principles of drug action,all types of drug receptor complex interactions very useful to students and post graduates..
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
3. General Principles of Drug Actions
• DRUGS DO NOT CREATE A NEW FUNCTION
IN THE CELL or TISSUES
• They can only MODIFY or
SUBSTITUTE for
a function already existing in the cell
WHAT ALL THE DRUGS CAN DO?
4. General Principles of Drug Actions
In a Host cell / tissue, DRUGS CAN -
• STIMULATE: Selectively a specific function of
a specialized cell;
e.g. Ach Increase the Salivary Secretion
• INHIBIT: Selectively a specific function of a
specialized cell;
e.g. Ach Inhibits the heart
Same Drug may Inhibit a function in one tissue
and Stimulate a function in another tissue
e.g. Adrenaline Stimulates Heart but
Inhibits Intestinal smooth muscles
5. General Principles of Drug Actions
In the Host cell DRUGS CAN -
• IRRITATE: Nonselectively stimulate many
functions in a Nonspecialized tissue :
Low dose Beneficial effect, but
High dose Harmful effect, e.g. Counterirritants
• REPLACE: A deficient function in a Specialized
cell, e.g. Insulin in Diabetes;
Vit. B12 in Pernicious anemia.
In a Foreign Invader Cell, DRUGS CAN
Stimulate / Inhibit / Irritate & thereby Selectively
the Organism without adversely affecting Host
Cell called ANTI-INFECTIVE action
e.g. Chemotherapy drugs
6. • Drugs ACT on some Biochemical / Physiological
/ Molecular processes of the cell, (which is Not
Necessarily Visible Ordinarily).
= Drug Action
(Molecular actions are often referred to as
“Mechanism of Action”)
• This molecular / cellular ACTION, through
complex sequences, ultimately causes an
EFFECT (Visible / Explicit) on organ systems
= Drug Effect
Pharmacodynamics is the study of both parts:
i.e. ACTION – EFFECT Sequence
HOW EXACTLY does the drug
do, what it does, when it gets there.
7. Drug Mechanisms
Drugs can act on / through –
• PROTEIN Targets
• RECEPTORS
• ENZYMES
• NON-PROTEIN Targets / mechanisms
Majority of Drugs act through RECEPTORS
DRUG – RECEPTOR INTERACTIONS
9. Drug-RECEPTOR Interactions:
RECEPTORS – what are they?
• Langley (1878) suggested presence of specific interaction
mechanisms/sites after observing SPECIFIC antagonistic
interactions between ‘Pilocarpine & Atropine’
• RECEPTORS -
• Macromolecular PROTEIN/PEPTIDE structures
• On the Cell Surface, or Transcellular or Intra-cellular
• Have SPECIFIC 3-D structure & Binding properties
• Regulate critical Cell Functions – e.g.
Enzyme activity
Permeability of cell (wall, membrane, etc)
Ion Channels activity
Carrier functions
Template Function, etc.
10. • LIGAND: (*Latin: Ligare = Bind)
Is a Molecule that Selectively binds to ‘a Specific’
Receptorthis binding property is called AFFINITY
Molecule with a different configuration wo’nt fit / bind
Ligands of different configurations will have AFFINITY
for ONLY their ‘respective’ Receptors
Ligand Receptor
Effective
Ligand-Receptor
Interaction
Works like Lock and Key principle.
“Wrong Shaped” Key doesn’t Fit
Drug-RECEPTOR Interactions - contd:
Other
Molecule
11. Agonist
Molecule
Receptor
Agonist-Receptor
Interaction
Lock and key mechanism;
Only Matching Key Opens (or
Activates) Lock
AGONIST:
• A Ligand molecule, which after binding, to receptor, can
“Activate” a Cell Function & cause MAXIMAL RESPONSE
property called INTRINSIC ACTIVITY
• AGONIST = AFFINITY + full INTRINSIC ACTIVITY
Drug-RECEPTOR Interactions - contd:
13. Antagonist Receptor
Antagonist-Receptor
Complex
DENIED!
AgAgAg
Antagonist blocks
Agonist action
ANTAGONIST:
• A Ligand molecule which binds, but can NOT “Activate” a
cell function No Action-effect Sequence (Response)
• But by binding to Receptor, it prevents Agonist-binding
• ANTAGONIST = AFFINITY + NO INTRINSIC ACTIVITY
Drug-RECEPTOR Interactions - contd:
14. Antagonist Receptor
Antagonist-Receptor
Complex
Antagonist can be dislodged
from receptor if Agonist conc.
is sufficiently increased (and
vice versa) Competitive
Antagonism
COMPETITIVE ANTAGONIST:
• If Antagonist binds with receptor thru weak bonds, higher
conc. of Agonist can over-ride/displace Antagonist
• Such interaction is called Competitive Antagonism
• Such Antagonist & Agonist are usually chemically similar
Drug-RECEPTOR Interactions - contd:
Agonist-Receptor
Interaction
16. Drug-RECEPTOR Interactions - contd:
PARTIAL AGONIST:
• A Ligand molecule which ONLY PARTIALLY “Activates” a
cell function cause only Submaximal Response (not a
Full Response) acts as ‘Weak’ agonist when given alone
• But will prevent a FULL AGONIST from binding with the
receptor Acts as Antagonist to a FULL AGONIST
• PARTIAL AGONIST = AFFINITY + INCOMPLETE /PARTIAL
INTRINSIC ACTIVITY
INVERSE AGONIST:
• Ligand has AFFINITY and “OPPOSITE AGONIST ACTION”
• Intrinsic activity causes Response that is Opposite to the
normally expected response. In fact “Inverse agonists”
can reduce receptor activity below basal levels observed
in the absence of bound ligand
Benzodiazepines -BDZAgonist (Diazepam)Anxiolytic
Beta-Carbolines Anxiogenic thru BDZ receptors
Inverse Agonist …….. (See later)
17. UP-REGULATION & DOWN REGULATION OF RECEPTORS:
• Continuous Exposure to the Agonist leads to DOWN-
REGULATION of the receptors. The receptor synthesis by
the cell decreases, and existing receptors are internalized
and presented to lysosomes for destruction.
• Down-Regulation leads to Decreased Response to the
agonists.
• Conversely Prolonged lack of exposure of receptors to
the Agonist leads to UP-REGULATION. More receptors
are synthesised by the cell and expressed on the surface.
• Up-Regulation leads to Restoration of, or an Enhanced,
Response.
• Examples: Clinical Response to Beta2-agonists in Asthma
decreases on continuous use. Response is restored on
discontinuation of drug for some time. Corticosteroids
can help RESTORE (upregulate) Beta2-receptors & the
response in asthmatics.
• Up- / Down-regulation are Gradual processes while a
rapid loss of response is called Desensitization.
21. 1. INTRACELLULAR RECEPTORS for Lipid Soluble agents
Ligand-Binding
Domain
DNA-binding Domain
(Zn fingers)
Transcription Domain
• Lipid soluble agents
(Corticosteroids, Sex
Steroids, Vitamin D,
Thyroxin etc) cross
into the cell & act on
Intracellular receptors
to activate them.
• Activated Receptors
bind with specific
“Response Elements”
(DNA Sequences) in
the nucleus.
22. INTRACELLULAR (Nuclear) RECEPTORS-contd.
• In the Nucleus, they Stimulate Transcription of
the Corresponding Genes mRNA synthesis
Specific Proteins are formed which lead to
RESPONSES. That is why they cause -
• SLOW-onset Therapeutic Response (0.5-many
hours)
• Effects (Therapeutic or ADRs) lasting LONGER
even after plasma Agonist levels fall to zero
• Recombinant techniques showed that Corticoids
remove “a restraining factor” on Transcription
process by binding to the specific component of
intracytoplasmic steroid receptor protein
23. Molecular M.O.A. of Corticoids
•Inabsence of Steroid, HSP90
(Heat Shock Protein) keeps
DNA-Binding Domain masked
•Steroid enters cytoplasm &
attaches toLigand-Binding
Domain that triggers the
release of HSP90
•This Unmasks DNA-binding &
Transcription-activating
domains of receptor-protein
folds (Zinc fingers)
•Specific mRNA synthesis
causes protein synthesis
whichcause RESPONSES
mRNA
Response
Proteins
Intracellular
Receptor for
Corticoids
25. γ γ
Inactive Monomers
Enzyme
Domain
Recog-
nition
Domain
Ligand Domain
α α
β β
Transmembrane Receptor
protein consist of –
• (a) Extracellular Ligand-
Binding domain (α);
• (b) Trans- & Intracellular
‘β’ domain
• Enzyme (Kinases)
Domain aminoacids (‘γ’)
lie in association with ‘β’
domain
• The inactive receptors
existing as MONOMERS
• Agonist binding causes
Monomers to DIMERIZE
Out
In
Cell Membrane
2. ENZYME-LINKED TRANSMEMBRANE (KINASE) RECEPTORS
26. γγγ γ
ENZYME-LINKED KINASE RECEPTORS - contd
Inactive Monomers
Enzyme
Kinases
Recog-
nition
Domain
Ligand Domain
P P
Substrate (s) S-Phos
ATP ADP
Ligand
α α
β β
Active
Dimer
• Ligand binding: ‘Inactive Monomers’‘Dimerize’ (activated)
• Activated Enzymes Phosphorylate specific AA residues ‘γ’ in
the substrate (Tyrosine for Insulin) Responses
Out
In
Cell Membrane
27. Kinase-linked receptors
•Receptors for various growth factors
incorporate tyrosine kinase in their
intracellular domain.
•Cytokine receptors have an intracellular
domain that binds and activates cytosolic
kinases when the receptor is occupied.
•The receptors all share a common
architecture, with a large extracellular
ligand-binding domain connected via a
single membrane-spanning helix to the
intracellular domain.
28. Kinase-linked receptors
• Signal transduction generally involves
dimerisation of receptors, followed by
autophosphorylation of tyrosine residues.
The phosphotyrosine residues act as
acceptors for the SH2 domains of a variety
of intracellular proteins, thereby allowing
control of many cell functions.
• They are involved mainly in events
controlling cell growth and differentiation,
and act indirectly by regulating gene
transcription.
29. Kinase-linked receptors
•Two important pathways are:
•the Ras/Raf/mitogen-activated protein
(MAP) kinase pathway, which is important
in cell division, growth and differentiation
•the Jak/Stat pathway activated by many
cytokines, which controls the synthesis
and release of many inflammatory
mediators.
•A few hormone receptors (e.g. atrial
natriuretic factor) have a similar architecture
and are linked to guanylate cyclase.
33. 3. LIGAND GATED RECEPTOR LINKED ION CHANNELS
• Also called Ionotropic Receptors
• 4-5 Transmembrane peptide sequences
• Ligand binds to Extracellular Ag-binding domain
• Transmembrane Domain enclose an Ion Channel
in Center
• Ex: Ach-Nicotinic-Receptors Na+ Ion
GABAA-Receptors Cl- Ion
34. • N-Ach-R consists of 5 subunits (2α and 1 each β, γ, δ)
which form a cluster around a Central Trans-membrane
Pore
• There are 2 Ach-binding sites in Extracellular part of
receptor at the interface between the α- δ, and α- γ
adjoining subunits.
α-helices forming gate
Ach-Nicotinic Receptor
Pore 0.7 nm diameter
35. • The lining of PORE is rich in negatively charged
amino -acids, which makes the pore Cation-selective.
• Kinked ‘α’ helices form the GATE
• When Ach binds, KINKS straighten out or swing out
of way
• This opens channel pore for Na+ influx results in
Depolarization.
α-helices forming gate
Ach-Nicotinic
Receptor
-ve Charged
Aminnoacids
36. B G
Cl-
Cl-
Cl- Cl-
Cl- Cl-
LIGAND GATED GABAA-RECEPTOR- Cl- CHANNELS
• Benzodiazepines (BDZ) [B] are Anxiolytic / Sedatives
Agonists on the BDZ-receptors
• Given alone, however, they do not affect Cl- ion influx
(necessary for Hyperpolarisation)
• GABA [G] acts as Agonists on GABAA-R and opens Cl-
channels Influx of Cl- ions Hyperpolarize Cell
Anxiolytic / Sedative
37. GB
Cl-
Cl-
Cl-
Cl-
Cl-
LIGAND GATED RECEPTOR LINKED ION CHANNELS-contd
• When Benzodiazepines [B] and GABA [G] act together,
Cl- ion influx is more efficient than that with GABA alone
• Thus BDZ effects (Anxiolytic, Hypnotic …) occur by
Agonist action on BDZ receptors, which FACILITATE
(Potentiate) GABA action on Chloride Channels
• BDZ-R can also bind with ‘Agonists’ like β-Carbolines
which cause Closure of Cl- Channel INVERSE AGONIST
[IA] ANXIOGENIC / CONVULSIOGENIC
G
Cl-
Cl-
Cl-
IA
38. G
Cl-
Cl-
Cl-
F
B
• Flumazenil, [F] BDZ-R Antagonist, blocks BDZ-
Receptors and prevents effect of BDZ [B]. Can be
used to Reverse Overdose with Benzodiazepines
• Flumazenil can block BDZ-R in both states of
conformation – Agonist well as Inverse Agonist
conformations i.e. Can block effects of BDZ as
well as β-Carbolines
G
Cl-
Cl-
Cl-
F
IA
LIGAND GATED RECEPTOR LINKED ION CHANNELS-contd
39. Drug Binding Sites in Voltage Gated Na+ Channels
• Ion Channels have
Muliple sites for Ligand
acting directly on it
• Ion Channels are also
affected INDIRECTLY by
ligands
GPCRs thru 2nd
Messengers system
e.g. Opioids & β-adr.
affect Ca++ and K+
Channels
Intracellular signals
e.g. Sulfonylureas on
ATP-gated K+
channels
41. 4. G-PROTEIN COUPLED RECEPTORS (GPCRs)
• Sometimes called Metabotropic
Receptors
• Hepta-helical (7 Transmembrane
loops) Receptors
• G-Proteins are located on the
intracytoplasmic face of cell
membrane along with GDP
• Called G-Proteins as they interact with GDP/GTP
• Agonist binds with specific Extracellular Domain
of GPCReceptor
• G-Prot are GOPHER (Go Between) Proteins which
carry ‘Ligand-R interaction’ signal to EFFECTORS
by diffusing within the cytoplasm
Ag-Binding
Domain
G-Protein
Coupling
Domain
43. G-PROTEIN COUPLED RECEPTORS (GPCR)
• G-Proteins are TRIMERS – consist of α, β and γ
subunits.
• Resting State: Trimer is attached to cell membrane
‘distant from receptor’ & GDP is anchored to α-
subunit.
• When Ag acts on Extracellular R-Domain, GTP
displaces GDP
• This activates “α-subunit+GTP” to diffuse away “to
the Effectors and activate them”. The βγ complex
can also bind with effectors.
• The Effectors are usually Enzymes or Ion Channels
• Many subtypes of G-Proteins – Gs, Gi, Gq etc, exist.
Ligands interact with different receptors thru
different G-Prot subtypes causing different end-
results (responses).
44. SOME TARGETS FOR G-PROTEINS
• Adenylyl cyclase, the enzyme responsible for
cAMP formation
• Phospholipase C, the enzyme responsible for
inositol phosphate and diacylglycerol (DAG)
formation
• Ion channels, particularly calcium and potassium
channels
• Rho A/Rho kinase, a system that controls the
activity of many signalling pathways controlling cell
growth and proliferation, smooth muscle
contraction, etc.
45. E1 E2
βγ
Rec
GDP
α
G-Prot
GTP
E1 E2
βγ
Rec
GDP
α
G-Prot
GTP
Resting State
G-Prot Unattached
Ligand Receptor
Activates G-Prot
E1 E2
βγ
Rec
GTP
α
2nd Messengers /
Ion Channels
RESPONSE
E1 E2
Rec
α
GDP
GTP
G-Prot
(Hydrolysis)
βγ
G-Prot Activate
Effectors
Back to Resting State
G-Proteins
Coupled
Receptors
+ P
46. EFFECTS OF G-Protein Receptor-Ag Interaction
G-PROTEIN MEDIATED EFFECTS mostly involve
generation of Chemicals called 2nd Messengers:
(a) Activation of Adenylyl Cyclase - cAMP pathway:
Binding to β-adrenoceptors adenylyl cyclase
thru the Stimulatory G-Protein (Gs) which causes
dissociation of its ‘αs-subunit’ charged with GTP.
‘Charged αs-subunit’ activates adenylyl cyclase
synthesis of cAMP.
The cAMP levels produce –
* Cardiac contractility
* Smooth muscle relaxation (Bronchi, Blood
Vessels, Gut, Uterus), and
* Glycogenolysis
Ex. of drugs cAMP Glucagon;
β-Adrenergic drugs (Adrenaline, Salbutamol);
Adenylyl Cyclase activity is by Muscarinic
drugs thru Gi-subtype G-Proteins.
47. EFFECTS OF RECEPTOR OCCUPATION BY AGONISTS
G-PROTEIN MEDIATED EFFECTS- 2nd Messengers:
(b) Phospholipase-C: IP3 – DAG Pathway:
Lead to Contraction, Secretion, Transmitter
Release, Neuronal Excitability, etc.
Ex: α1–Adrenergic, H1-Histaminic, M1-Muscarinic
Effects.
A ligand can produce different effects in
different cells by interacting with different
subtypes of G-Proteins:
e.g. Catecholamines respond to Stress by
Increasing Heart Rate thru Gs-coupled
β-receptors & Vasoconstriction in skin
thru Gq-coupled α1-receptors
(c) Channel Regulation:
Ca++, Na+, K+ channels Open / Close .
49. βM3
Gq Gs
Aden
Cycl M2
Gi
ATP cAMP
+ _
_
DAG IP3
Ca++
PLC-β
Contraction of Sm. M.
_
G-Proteins mediated 2nd Messengers in Smooth Muscles
Cardiac , Sm.
M. Relaxation,
Glycogenolysis
Protein Kinase C
G-Proteins subtypes
Gs – Stimulates Target enzymes
Gi – Inhibitory effects
Gq – Activates Phospholipase-C release
IP3 Ca++ release & PKC
50. SPARE RECEPTORS
Clark (1930s) observed that –
• Adrenaline / Acetylcholine / Histamine can still produce
Maximal Response when most receptors have been blocked
by Irreversible Antagonist.
• Receptors are said to be "spare" if maximal biologic
response can be elicited at Ag-concentration that does not
occupancy the full complement of available receptors.
• It really indicates that very small % of available receptors are
needed to produce maximal response.
• Spareness of receptors determines the sensitivity of tissue.
• Experimentally, spare receptors may be demonstrated by
using “Irreversible Antagonist” to prevent binding of Agonist
to a proportion of available receptors and showing that high
concentrations of agonist can still produce an undiminished
maximal response.
51. RECEPTOR HETROGENEITY & SUBTYPES
• Receptors within a given family generally occur in several
molecular varieties, or subtypes, with similar architecture but
significant differences in their AMINOACID sequences.
• This results in variation in their pharmacological properties.
• Examples: Ach-N Nicotinic-N (nervous tissue) &
Nicotinic-M (skeletal muscles)
Beta-adrenoceptors β1, β2, β3
Alpha-adrenoceptors α1 & α2 and their further
subtypes α1A, α1C, etc
• Different subtypes / isoforms allow more selective agonists &
antagonists for use in specific disorders
• New subtypes are being discovered regularly, specially after
gene-splicing technology and cloning of receptors
52. SILENT RECEPTORS
• Drugs can bind to molecules that have no direct relation with
the action-effect sequence.
• These binding sites are indeed termed as “Sites of Loss” as
this fraction is not available for action.
• These sites are also called Drug Acceptors
• Most important example is “Binding to Plasma Proteins”
• Other sites can be Tissue Binding sites in those tissues
where the primary action of drug is not expected
• These sites have been called as “SILENT RECEPTORS”
• Indirectly these bindings affect drug response as bound
fraction acts as Storage Site from where drug is released into
active free form as the free fraction levels decline
• Highly plasma protein bound drugs show features like Slow
Onset & Prolonged Duration of action, more displacement
Drug-Drug Interactions, etc.
53. ORPHAN RECEPTORS
• In 1970s, the-then theoretical receptors began emerging as
biochemical realities with “labeling of receptors”.
• This led to extraction & purification of receptor material – first
of them was N-Ach receptors from Electric Organs of Rayfish
& Electric eels.
• Simultaneously venoms of snakes of cobra family were
found to have polypeptides that bound avidly with the N-Ach
receptors.
• After isolation / purification of receptor proteins, their
aminoacid sequence was deciphered.
• Gene cloning allowed hundreds of subtypes of receptors to
be prepared – so much so that the ligands for many gene-
cloned receptors are yet to be found - & their role remains
unknown.
• Such receptors are called ORPHAN RECEPTORS. Some
day their specific ligands are found & used in medicine.
58. Non-receptor Mechanisms – Chemical actions
• Combining With Other Chemicals
• Antacids
• Antiseptic effects of alcohol, phenol
• Chelation of heavy metals
63. Dose Response Relationships
• Potency
• Absolute amount of drug required to
produce an effect
• More potent drug is the one that
requires lower dose to cause same
effect
65. Dose Response
Relationships
• Threshold (minimal) dose
• Least amount needed to produce
desired effects
• Maximum effect
• Greatest response produced
regardless of dose used
66. Dose Response Relationships
Which drug has the lower threshold dose?
Effect
Dose
A
B
Which has the greater maximum effect?
A
B
Therapeutic
Effect
67. Dose Response Relationships
• Loading dose
• Bolus of drug given initially to
rapidly reach therapeutic levels
• Maintenance dose
• Lower dose of drug given
continuously or at regular intervals
to maintain therapeutic levels