Pharmacology 2060A/B Lecture Notes - Lecture 8: Opioid, Opiate, Histamine

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apricotfly938

3 Mar 2016

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Module 8 - pharmacodynamics drug receptor interactions. Theories of drug receptor interactions. 2 receptor theories that we use to describe drug receptor interactions: the simple occupancy theory, the modified occupancy. 1 the intensity of a drugs response is proportional to the number of receptors occupied. 2 the maximal response occurs when all the receptors are occupied. 2 drugs act at the same receptor should produce the same effect. We know this b/c there are many drugs that act at the same receptor yet have different efficacies. Some characteristics of drug receptor interactions cannot be accounted for by the simple occupancy theory. Modified occupancy theory affinity. Affinity attraction that a drug has for its receptor. High affinity = highly attracted to their receptor and therefore bind to the receptor effectively even at low concentration. Low affinity = weakly attracted to their receptor and therefore bind ineffectively to the receptor even at high concentration.

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2. The receptor that binds the steroid hormone testosterone is located in the cytoplasm of its target cells. Vasopressin is a peptide hormone (nine amino acids long) that stimulates water reabsorption in the kidney. Its receptor is an integral protein in which the domain of the receptor responsible for binding vasopressin is located on the extracellular side of the cell membrane.

a) Why must the vasopressin-binding domain of the vasopressin receptor be located on the outside of a cell while the testosterone receptor can be located within a cell? Neither hormone binds to another molecule before it binds to its receptor. (If you are curious, the vasopressin sequence is Gly-Arg-Pro-Cys-Asn-Gln-Phe-Tyr-Cys â you can look up those side chains if you want.)

b) What type or types of amino acids do you expect to predominate in the vasopressin-binding domain of the vasopressin receptor? What type or types of amino acids do you expect to find the transmembrane region of the vasopressin receptor (this region has several alpha helices passing through the membrane)? Explain your reasoning.

c) Why are alpha-helices commonly found in the transmembrane region of integral proteins?

crimsonbear193

The binding of platelet derived growth factor (PDGF) to the PDGF receptor stimulates phosphorylation of 8 tyrosines in the receptor's cytoplasmic domain. The enzyme phosphatidylinositol 3'kinase (PI 3-kinase) binds to one or more of the phophotyrosines through its SH2 domains and is thereby activated. To identify the activation phosphotyrosines, you synthesize 8 pentapetides that contain the critical tyrosines (at the N-terninus) in their phosphorylated or unphosphorylated forms. You then mix an excess of each of the various pentapeptides with phosphorylated PDGF receptor and PI 3-kinase. Immunoprecipitation of the PDGF receptor will bring down any bound PI 3-kinase, which can be assayed by its ability to add 32P-phosphate to its substrate.

A) Draw a flow diagram showing how this assay works.

B) Do your results support the notion that PI-kinase binds to phosphotyrosines in the activated PDGF receptor? Why or why not?

C) THe amino acid sequences of the PDGF receptor pentapeptide tested above (number accodingly to the position of tyrosine in the PDGF receptor) and peptide segments that are known to bind to PI 3-kinase in other activated receptors are shown below. Which amino acid residues are most important and why?

684 YSNAL YMMMR (FGF receptor)

708 YMDMS YTHMN (insulin receptor)

719 YVPML YEVML (hepatocyte growth factor receptor)

731 YADIE YMDMK (steel factor receptor)

739 YMAPY YVEMR (CSF-1 receptor)

743 YDNYE

746 YEPSA

755 YRATL

graycod585

receptor	Agonist	antagonist


a1	Norephinephrine	Phenylephrine
a2	Phenoxybenzamine	Prazosin
B1	Clonidine	Yohimbine
	Norephinephrine	Propranolol
	Epinephrine	Metoprolol
	Isoproterenol
	Dobutamine
B2	Epinephrine	Proranolol
	Norepinephrine	Butoxamine
	Isoproterenol
	Albuterol


Nicotinic	Ach	Curare
	Nicotine
		Hexamethonium
Muscarinic	Ach	Atropine

Assume all the chemicals in the table are available to you.

You are given a piece of smooth muscle tissue, you stimulate it with Norepinephrine and find the muscle responds with contractions. Your hypothesis is that the muscle contraction is caused by the activation of Î±1 adrenergic receptors. Now you need to design an experiment protocol to test your hypothesis.

Background knowledge: The figure below is an experiment setup, the red tissue in the organ bath is the smooth muscle tissues. In this kind of experiment smooth muscle tissue is minimally stretched vertically by two hooks or clips in the organ bath filled with physiological saline solution (PSS). Agonist is added to the PSS to challenge the muscle tissue, muscle contraction is sensed by a force transducer at the top and force is recorded by a computer. Adding antagonist before adding agonist blocks agonist action. PSS may or may not be changed, it depends on your purposes, e.g. if you want to block a type receptors, then you do not want change PSS after you add antagonist to the PSS. Your correct step is that you add antagonist to PSS, wait some time, and add agonist, you keep both antagonist and agonist in the PSS so that you can judge if the receptor blockage by antagonist abolish the agonist action.

The key to this assignment is that you eliminate possible cross-activities of agonists. Cross-activity means an agonist activate more than one types of receptors, you need block each type of the receptor in order to see what type of the receptor is activate to cause contraction. This muscle tissue can have both Î± and Î² receptor types and their subtypes, you need to demonstrate convincingly that you only stimulate Î±1 receptors.

Write an experimental protocol to demonstrate your work, for each step in the protocol you write the chemical(s) you add, why you add, what result you are expecting to see e.g. contract, relax, no response. If the step is to wash the tissue with fresh PSS, then you do not need to indicate the responses.

Here is an example of the answer.

step	chemical added	response
1.	epinephrine, activate alpha and beta receptors,	blood vessel ring contract slightly.
2.	wash with PSS
3.	alpha receptor antagonist and norepinerphine, block NE activating alpha receptor.	blood vessel ring should not contract.
4.	wash with PSS
5.	â¦	â¦
6.	â¦	â¦

Discuss your protocol to show the relation between activation of Î±1 receptors and the vascular smooth muscle contraction.Design the experiemnt and its conclusion/ results.

Pharmacology 2060A/B Lecture Notes - Lecture 8: Opioid, Opiate, Histamine

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