Outline

1
Outline

• 28.1 Messenger Molecules
• 28.2 Hormones and the Endocrine System
• 28.3 How Hormones Work Epinephrine and
  Fight-or-Flight
• 28.4 Amino Acid Derivatives and Polypeptides as
  Hormones
• 28.5 Steroid Hormones
• 28.6 Neurotransmitters
• 28.7 How Neurotransmitters Work Acetylcholine,
  Its Agonists and Antagonists
• 28.8 Histamine and Antihistimines
• 28.9 Serotonin, Norepinephrine, and Dopamine
• 28.10 Neuropeptides and Pain Relief
• 28.11 Drug Discovery and Drug Design

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Goals

• What are hormones, and how do they function?
• Be able to describe in general the origins,
  pathways, and actions of hormones.
• 2. What is the chemical nature of hormones?
• Be able to list, with examples, the different
  chemical types of hormones.
• 3. How does the hormone epinephrine deliver its
  message, and what is its major mode of action?
• Be able to outline the sequence of events in
  epinephrines action as a hormone.
• What are neurotransmitters, and how do they
  function?
• Be able to describe the origins, pathways, and
  actions of neurotransmitters.
• How does acetylcholine deliver its message, and
  how do drugs alter its function?
• Be able to outline the sequence of events in
  acetylcholines action as a neurotransmitter and
  give examples of its agonists and antagonists.
• Which neurotransmitters and what kinds of drugs
  play roles in allergies, mental depression, drug
  addiction, and pain?
• Be able to identify neurotransmitters and drugs
  active in these conditions.
• What are neurotransmitters, and how do they
  function?
• Be able to explain the general roles of
  ethnobotany, chemical synthesis, combinatorial
  chemistry, and computer-aided design in the
  development of new drugs.

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28.1 Messenger Molecules

• Coordination and control of vital functions are
  accomplished by chemical messengers.
• Hormones that arrive via the bloodstream or
  neurotransmitters released by nerve cells
  ultimately connect with a target.
• The message is delivered by interaction between
  the chemical messenger and a receptor.
• The receptor acts like a switch, causing some
  biochemical response to occur.

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28.1 Messenger Molecules

• Non-covalent attractions draw messengers and
  receptors together long enough for the message to
  be delivered, but without any permanent chemical
  change to the messenger or the receptor.

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28.1 Messenger Molecules

• Hormones are the chemical messengers of the
  endocrine system, and are produced by glands and
  tissues often at distances far from their
  ultimate site of action.
• Hormones travel through the bloodstream to their
  targets and the responses they produce can
  require anywhere from seconds to hours to begin,
  but action or actions they elicit, however, may
  last a long time and can be wide-ranging.
• A single hormone will often affect many different
  tissues and organsany cell with the appropriate
  receptors is a target.

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28.1 Messenger Molecules

• Insulin is a hormone secreted by the pancreas in
  response to elevated blood glucose levels.
• At target cells throughout the body, insulin
  accelerates uptake and utilization of glucose.
• In muscles, it accelerates formation of glycogen,
  a glucose polymer that is metabolized when
  muscles need quick energy.
• In fatty tissue, it stimulates storage of
  triacylglycerols.

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28.1 Messenger Molecules

• The chemical messengers of the nervous system are
  neurotransmitters.
• The electrical signals of the nervous system
  travel along nerve fibers, taking only a fraction
  of a second to reach their highly specific
  destinations.
• Most nerve cells do not make direct contact with
  the cells they stimulate. A neurotransmitter must
  carry the message across the tiny gap separating
  the nerve cell from its target.

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28.1 Messenger Molecules

• Because neurotransmitters are released in very
  short bursts and are quickly broken down or
  reabsorbed by the nerve cell, their effects are
  short-lived.
• The nervous system is organized so that nearly
  all of its vital switching, integrative, and
  information-processing functions depend on
  neurotransmitters.
• Neurotransmitters are typically synthesized and
  released very close to their site of action.

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28.1 Messenger Molecules

• Homeostasis
• Homeostasis is as important to the study of
  living things as atomic structure is to the study
  of chemistry.
• Conditions such as body temperature, the
  availability of chemical compounds that supply
  energy, and the disposal of waste products must
  remain within specific limits for an organism to
  function properly.
• Sensors track the internal environment and send
  signals to restore proper balance if the
  environment changes. If oxygen is in short
  supply, a signal is sent that makes us breathe
  harder. When we are cold, a signal is sent to
  constrict surface blood vessels and prevent
  further loss of heat.
• At the chemical level, the concentrations of ions
  and many different organic compounds are
  maintained so they stay near normal levels.
• The predictability of the concentrations of such
  substances is the basis for clinical
  chemistrythe chemical analysis of body tissues
  and fluids.
• In the clinical lab, various tests measure
  concentrations of significant ions and compounds
  in blood, urine, feces, spinal fluid, or other
  samples from a patients body. Comparing the lab
  results with norms (average concentration
  ranges in a population of healthy individuals)
  shows which body systems are struggling, or
  possibly failing, to maintain homeostasis.

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28.2 Hormones and the Endocrine System

• The endocrine system includes all cells that
  secrete hormones into the bloodstream.
• Some are found in organs that also have
  non-endocrine functions others occur in glands
  devoted solely to hormonal control.
• Hormones do NOT carry out chemical reactions.
  Hormones are simply messengers that alter the
  biochemistry of a cell.

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28.2 Hormones and the Endocrine System

• The major endocrine glands are the thyroid gland,
  the adrenal glands, the ovaries and testes, and
  the pituitary gland.
• The hypothalamus, a section of the brain just
  above the pituitary gland, is in charge of the
  endocrine system. It communicates with other
  tissues in three ways
• Direct neural control A nervous system message
  from the hypothalamus initiates release of
  hormones by the adrenal gland.

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28.2 Hormones and the Endocrine System

• Direct release of hormones Hormones move from
  the hypothalamus to the posterior pituitary
  gland, where they are stored until needed.
• Indirect control through release of regulatory
  hormones Regulatory hormones from the
  hypothalamus stimulate or inhibit the release of
  hormones by the anterior pituitary gland. Many of
  these pituitary hormones in turn stimulate
  release of still other hormones by their own
  target tissues.

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28.2 Hormones and the Endocrine System

• Hormones are of three major types (1) amino acid
  derivatives (2) polypeptides, which range from
  just a few amino acids to several hundred amino
  acids and (3) steroids, which are lipids with
  the distinctive molecular structure based on four
  connected rings common to all sterols.

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28.2 Hormones and the Endocrine System
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28.2 Hormones and the Endocrine System

• Upon arrival at its target cell, a hormone must
  deliver its signal to create a chemical response
  inside the cell.
• The steroid hormones are nonpolar, so they can
  enter the cell directly by diffusion.
• Once within the cells cytoplasm, a steroid
  hormone encounters a receptor molecule that
  carries it to its target, DNA in the nucleus of
  the cell.
• The result is some change in production of a
  protein governed by a particular gene.

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28.2 Hormones and the Endocrine System
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28.2 Hormones and the Endocrine System

• Polypeptide and amine hormones cannot cross the
  hydrophobic cell membranes.
• They deliver their messages by bonding
  noncovalently with receptors on cell surfaces.
  The result is release of a second messenger.
• In general, three membrane-bound proteins
  participate in release of the second messenger
• Interaction of the hormone with its receptor
  causes a change in the receptor.
• This stimulates the G protein to activate an
  enzyme that participates in release of the second
  messenger.

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28.3 How Hormones Work Epinephrine and Fight
or Flight

• The main function of epinephrine in a startle
  reaction is a dramatic increase in the
  availability of. The time elapsed from initial
  stimulus to glucose release into the bloodstream
  is only a few seconds.

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28.3 How Hormones Work Epinephrine and Fight
or Flight

• Epinephrine acts via cyclic adenosine
  monophosphate (cyclic AMP, or cAMP), an important
  second messenger. The sequence of events in this
  action, illustrates one type of biochemical
  response to a change in an individuals external
  or internal environment.

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28.3 How Hormones Work Epinephrine and Fight
or Flight

• Epinephrine binds to a receptor on the surface of
  a cell.
• The hormonereceptor complex activates a nearby G
  protein embedded in the interior surface of the
  cell membrane.
• GDP (guanosine diphosphate) associated with the G
  protein is converted to GTP (guanosine
  triphosphate) by addition of a phosphate group.
• The G proteinGTP complex activates adenylate
  cyclase, an enzyme that also is embedded in the
  interior surface of the cell membrane.
• Adenylate cyclase catalyzes production within the
  cell of the second messengercyclic AMPfrom ATP.
• Cyclic AMP initiates reactions that activate
  glycogen phosphorylase, the enzyme responsible
  for release of glucose from storage.
• When the emergency has passed, cyclic AMP is
  converted to ATP.

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28.3 How Hormones Work Epinephrine and Fight
or Flight
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28.3 How Hormones Work Epinephrine and Fight
or Flight

• Epinephrine also increases blood pressure, heart
  rate, and respiratory rate. It also decreases
  blood flow to the digestive system and
  counteracts spasms in the respiratory system.
• The resulting effects make epinephrine the most
  crucial drug for treatment of anaphylactic shock.
• Anaphylactic shock is the result of a severe
  allergic reaction it is an extremely serious
  medical emergency.
• The major symptoms include a severe drop in blood
  pressure due to blood vessel dilation and
  difficulty breathing due to bronchial
  constriction. Epinephrine directly counters these
  symptoms.

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28.4 Amino Acid Derivatives and Polypeptides as
Hormones

• Several amino acid derivatives classified as
  hormones because of their roles in the endocrine
  system are also synthesized in neurons and
  function as neurotransmitters in the brain.

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28.4 Amino Acid Derivatives and Polypeptides as
Hormones

• Thyroxine is one of two iodine-containing
  hormones produced by the thyroid gland.
• Thyroxine is a nonpolar compound that can cross
  cell membranes and enter cells, where it
  activates the synthesis of various enzymes.
• When dietary iodine is insufficient, the thyroid
  gland compensates by enlarging. A greatly
  enlarged thyroid gland (a goiter) is a symptom of
  iodine deficiency.

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28.4 Amino Acid Derivatives and Polypeptides as
Hormones

• In developed countries where iodine is added to
  table salt, goiter is uncommon.
• In some regions of the world, iodine deficiency
  is a common and serious problem that results in
  goiter and severe mental retardation in infants
  (cretinism).

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28.4 Amino Acid Derivatives and Polypeptides as
Hormones

• Polypeptides
• Polypeptides are the largest class of hormones.
• They range widely in molecular size and
  complexity.

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28.5 Steroid Hormones

• Sterol hormones, referred to as steroids, are
  divided according to function into three types
  mineralocorticoids and glucocorticoids and the
  sex hormones.
• The two most important androgens, are
  testosterone and androsterone.

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28.5 Steroid Hormones

• Estrone and estradiol, the estrogens, are
  synthesized from testosterone.
• The progestins, principally progesterone, are
  released by the ovaries during the second half of
  the menstrual cycle.

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28.5 Steroid Hormones

• Anabolic steroids are drugs that resemble
  androgenic (male) hormones, such as testosterone.
  
• Many serious side effects can arise from abuse of
  anabolic steroids.
• Today, most organized sports have banned the use
  of these and other performance enhancing drugs.
• Despite bans, the use of roids is widespread in
  sports.

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28.5 Steroid Hormones

• Some athletes attempt to get around drug
  screenings by using designer steroidsidentificati
  on depends on knowing the compounds structure.
• Analysis of a synthetic steroid to determine its
  structure is easily done, and tests can be
  quickly developed.

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28.5 Steroid Hormones

• Plant Hormones
• Plants do not have endocrine systems or fluids
  that continuously circulate.
• Phhytohormones affect the cells in which they are
  synthesized.
• They may also reach nearby cells by diffusion or
  travel upward with water from the roots or
  downward with sugars made by photosynthesis in
  the leaves.
• A very simple alkene, ethylene gas, functions as
  a hormone in plants. At one time, citrus growers
  ripened oranges in rooms heated with kerosene
  stoves. When the stoves were replaced with other
  means of heating, the oranges no longer ripened.
  It turned out that ripening is hastened by the
  ethylene released by burning kerosene.
• Plants turn toward the sun, a phenomenon known as
  phototropism.
• Charles Darwin observed that covering the growing
  tips of the plants prevented phototropism. The
  explanation lies in the formation in the tip of
  an auxin, a hormone that travels downward and
  stimulates elongation of the stem. Auxin
  concentrates on the shady side of the stem,
  causing it to grow faster so that the stem bends
  toward the sun.
• Auxin is produced in seed embryos, young leaves,
  and growing tips of plants. Interestingly, plants
  synthesize auxin from tryptophan, the starting
  compound in the synthesis of several mammalian
  chemical messengers.
• An excessive concentration of auxin kills plants
  by overaccelerating their growth. The most
  familiar synthetic auxin, 2,4-D, is an herbicide
  that is widely used to kill broad-leaved weeds in
  this manner.

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28.6 Neurotransmitters

• Neurotransmitters are the chemical messengers of
  the nervous system.
• They are released by neurons and transmit signals
  to neighboring target cells.
• The target cells can be
• other nerve cells,
• muscle cells, or
• endocrine cells.

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28.6 Neurotransmitters

• Nerve cells that rely on neurotransmitters
  typically have a bulb-like body connected to a
  long, thin stem called an axon.
• Short, tentacle-like appendages, dendrites,
  protrude from the bulbous end of the neuron, and
  filaments protrude from the axon at the opposite
  end.
• The filaments lie close to the target cell,
  separated only by a narrow gapthe synapse.

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28.6 Neurotransmitters
35
28.6 Neurotransmitters

• A nerve impulse is transmitted along a nerve cell
  by variations in electrical potential.
• Chemical transmission of the impulse between a
  nerve cell and its target occurs when
  neurotransmitter molecules are released from a
  presynaptic neuron, cross the synapse, and bind
  to receptors on the target cell.
• The postsynaptic neuron then transmits the nerve
  impulse down its own axon until a
  neurotransmitter delivers the message to the next
  neuron or other target cell.

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28.6 Neurotransmitters

• Neurotransmitter molecules are synthesized in the
  presynaptic neurons and stored in vesicles, from
  which they are released as needed.
• After a neurotransmitter has done its job, it
  must be rapidly removed from the synaptic cleft
  so that the postsynaptic neuron is ready to
  receive another impulse.
• Either an enzyme available in the synaptic cleft
  inactivates the neurotransmitter, or the
  neurotransmitter is returned to the presynaptic
  neuron and placed in storage until it is needed
  again.

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28.6 Neurotransmitters

• Most neurotransmitters are amines synthesized
  from amino acids.

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28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists

• Acetylcholine is a neurotransmitter responsible
  for the control of skeletal muscles.
• It is also widely distributed in the brain.
• Nerves that rely on acetylcholine as their
  neurotransmitter are classified as cholinergic
  nerves.
• Acetylcholine is synthesized in presynaptic
  neurons and stored in their vesicles.

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28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists
40
28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists

• A nerve impulse arrives at the presynaptic
  neuron.
• The vesicles move to the cell membrane, fuse with
  it, and release their acetylcholine molecules.
• Acetylcholine crosses the synapse and binds to
  receptors on the postsynaptic neuron, causing a
  change in membrane permeability to ions.
• The resulting change initiates the nerve impulse
  in that neuron.
• With the message delivered, acetylcholinesterase
  present in the synaptic cleft catalyzes the
  decomposition of acetylcholine.
• Choline is absorbed back into the presynaptic
  neuron where new acetylcholine is synthesized.

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28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists

• Drugs and Acetylcholine
• Many drugs act at acetylcholine synapses.
• The action is at the molecular level, and it can
  be either therapeutic or poisonous.
• Pharmacologists classify some drugs as agonists,
  while others are antagonists.
• Many agonists and antagonists compete with normal
  signaling molecules for interaction with the
  receptor.

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28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists

• Botulinus toxin blocks acetylcholine release and
  causes botulism. 
• The toxin binds irreversibly to the presynaptic
  neuron, preventing acetylcholine release and
  causing death due to muscle paralysis.
• Black widow spider venom releases excess
  acetylcholine. 
• The synapse is flooded with acetylcholine,
  resulting in muscle cramps and spasms.
• Organophosphorus insecticides (antagonists),
  inhibit acetylcholinesterase. 
• All of the organophosphorus insecticides prevent
  acetylcholinesterase from breaking down
  acetylcholine within the synapse.

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28.7 How Neurotransmitters Work Acetylcholine,
Its Agonists and Antagonists

• Nicotine binds to acetylcholine receptors. 
• Nicotine at low doses is a stimulant (an agonist)
  because it activates acetylcholine receptors. The
  sense of alertness and well-being produced by
  inhaling tobacco smoke is a result of this
  effect. At high doses, nicotine is an antagonist.
  
• Atropine (an antagonist), competes with
  acetylcholine at receptors. 
• Atropine can be used for acceleration of
  abnormally slow heart rate, paralysis of eye
  muscles during surgery, and relaxation of
  intestinal muscles in gastrointestinal disorders.
  Most importantly, it is a specific antidote for
  acetylcholinesterase poisons.
• Tubocurarine (an antagonist), competes with
  acetylcholine at receptors.
• The alkaloid is used to paralyze patients in
  conjunction with anesthesia drugs prior to
  surgery.

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28.8 Histamine and Antihistamines

• Histamine is the neurotransmitter responsible for
  the symptoms of allergic reaction.
• Histamine is produced by decarboxylation of
  histidine.
• Antihistamines are histamine receptor
  antagonists.
• Histamine also activates secretion of acid in the
  stomach.

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28.9 Serotonin, Norepinephrine and Dopamine

• The Monoamines and Therapeutic Drugs
• Serotonin, norepinephrine, and dopamine are
  monoamines.
• All are active in the brain and all have been
  identified in various ways with mood, the
  experiences of fear and pleasure, mental illness,
  and drug addiction.
• There is a well-established relationship between
  major depression and a deficiency of serotonin,
  norepinephrine, and dopamine.

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28.9 Serotonin, Norepinephrine and Dopamine

• Amitriptyline is representative of the tricyclic
  antidepressants, which prevent the re-uptake of
  serotonin and norepinephrine from within the
  synapse.
• Phenelzine is a monoamine oxidase (MAO)
  inhibitor, one of a group of medications that
  inhibit the enzyme that breaks down monoamine
  neurotransmitters.
• Fluoxetine represents the newest class of
  antidepressants, the selective serotonin
  re-uptake inhibitors (SSRI). They inhibit only
  the re-uptake of serotonin. Most antidepressants
  cause unpleasant side effects fluoxetine does
  not.

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28.9 Serotonin, Norepinephrine and Dopamine

• Dopamine and Drug Addiction
• Dopamine plays a role in the brain in processes
  that control movement, emotional responses, and
  the experiences of pleasure and pain.
• Cocaine blocks re-uptake of dopamine from the
  synapse, and amphetamines accelerate release of
  dopamine. Studies have linked increased brain
  levels of dopamine to alcohol and nicotine
  addiction as well. The stimulation of dopamine
  receptors by drugs results in tolerance, which
  contributes to addiction.
• Marijuana also creates an increase in dopamine
  levels. The use of marijuana medically for
  chronic pain relief has become a controversial
  topic in recent years, as questions about its
  benefits and drawbacks are debated.

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28.10 Neuropeptides and Pain Relief

• Studies of opium derivatives revealed that these
  pain-killing substances act via specific brain
  receptors.
• The pentapeptides Met-enkephalin and
  Leu-enkephalin exert morphine-like suppression of
  pain. Structural similarity between
  Met-enkephalin and morphine make it likely that
  both interact with the same receptors.
• Natural pain-killing polypeptides that act via
  the opiate receptors are classified as
  endorphins.

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28.11 Drug Discovery and Drug Design

• Today ethnobotanists work in remote regions of
  the world to learn what indigenous people have
  discovered about the healing powers of plants.
• The technique of modifying a known structure to
  improve its biochemical activity was developed
  after cocaine was first used as a local
  anesthetic in 1884. Experiments with other
  benzoic acid esters in the early 1900s yielded
  benzocaine and procaine (novocaine), both still
  in use.

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28.11 Drug Discovery and Drug Design

• Combinatorial chemistry, arrived on the scene in
  1991. By combining reactants, dividing up the
  products, adding other reactants, and continuing
  this process, millions of related compounds can
  be synthesized.
• If the tertiary structure of an enzyme has been
  found and the active site identified, a computer
  can consult a database of quantitative
  information about drugreceptor interactions.
• Once potential inhibitors are identified, it is
  increasingly possible to design a molecule with
  just the right chemical and physical properties.

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Chapter Summary

• What are hormones, and how do they function?
• Hormones are the chemical messengers of the
  endocrine system.
• Under control of the hypothalamus they are
  released from various locations, many in response
  to intermediate, regulatory hormones.
• Hormones travel in the bloodstream to target
  cells, where they connect with receptors that
  initiate chemical changes within cells.

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Chapter Summary, Continued

• What is the chemical nature of hormones?  
• Hormones are polypeptides, steroids, or amino
  acid derivatives.
• Many are polypeptides, which range widely in size
  and include small molecules such as vasopressin
  and oxytocin, larger ones like insulin, and all
  of the regulatory hormones.
• Steroids have a distinctive four-ring structure
  and are classified as lipids because they are
  hydrophobic. All of the sex hormones are
  steroids.
• Hormones that are amino acid derivatives are
  synthesized from amino acids.
• Epinephrine and norepinephrine act as hormones
  throughout the body and also act as
  neurotransmitters in the brain.

53
Chapter Summary, Continued

• How does the hormone epinephrine deliver its
  message, and what is its mode of action?
• Epinephrine, the fight-or-flight hormone, acts
  via a cell-surface receptor and a G protein that
  connects with an enzyme, both of which are
  embedded in the cell membrane.
• The enzyme adenylate cyclase transfers the
  message to a second messenger, a cyclic adenosine
  mono-phosphate (cyclic AMP), which acts within
  the target cell.

54
Chapter Summary, Continued

• What are neurotransmitters, and how do they
  function?
• Neurotransmitters are synthesized in presynaptic
  neurons and stored there in vesicles from which
  they are released when needed.
• They travel across a synaptic cleft to receptors
  on adjacent target cells.
• Some act directly via their receptors others
  utilize cyclic AMP or other second messengers.
• After their message is delivered,
  neurotransmitters must be broken down rapidly or
  taken back into the presynaptic neuron so that
  the receptor is free to receive further messages.

55
Chapter Summary, Continued

• How does acetylcholine deliver its message, and
  how do drugs alter its function?
• Acetylcholine is released from the vesicles of a
  presynaptic neuron and connects with receptors
  that initiate continuation of a nerve impulse in
  the postsynaptic neuron.
• It is then broken down in the synaptic cleft by
  acetylcholinesterase to form choline that is
  returned to the presynaptic neuron where it is
  converted back to acetylcholine.
• Agonists, such as nicotine at low doses activate
  acetylcholine receptors and are stimulants.
• Antagonists, such as tubocurarine or atropine,
  which block activation of the receptors, are
  toxic in high doses, but at low doses are useful
  as muscle relaxants.

56
Chapter Summary, Continued

• Which neurotransmitters and what kinds of drugs
  play roles in allergies, mental depression, drug
  addiction, and pain?
• Histamine, an amino acid derivative, causes
  allergic symptoms. Antihistamines are antagonists
  with a general structure that resembles
  histamines, but with bulky groups at one end.
• Monoamines (serotonin, norepinephrine, and
  dopamine) are brain neurotransmitters. A
  deficiency of any of these molecules is
  associated with mental depression.
• Drugs that increase their activity include
  tricyclic antidepressants (for example,
  amitriptyline), monoamine oxidase (MAO)
  inhibitors (for example, phenelzine), and
  selective serotonin re-uptake inhibitors (SSRI)
  (for example, fluoxetine).
• An increase of dopamine activity in the brain is
  associated with the effects of most addictive
  substances. A group of neuropeptides acts at
  opiate receptors to counteract pain all may be
  addictive.

57
Chapter Summary, Continued

• What are some of the methods used in drug
  discovery and design?
• Ethnobotanists work to identify the medicinal
  products of plants known to native peoples.
• Chemical synthesis is used to improve on the
  medicinal properties of known compounds by
  creating similar structures.
• Combinatorial chemistry produces many related
  molecules for drug screening.
• Computer design is used to select the precise
  molecular structure to fit a given receptor.