Agonists, antagonists, inverse agonists — Transcript

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1. 0:00in this lesson we're going to make sure
2. 0:03that you really understand what an
3. 0:05Agonist is because we're going to be
4. 0:07talking about agonists all the way
5. 0:08through this chapter but also we're
6. 0:11going to be comparing that to what else
7. 0:14can happen at that receptor for instance
8. 0:17partial agonists antagonists and inverse
9. 0:21agonists it has a really broad overview
10. 0:24medications can generally be considered
11. 0:26agonists where they bind to the receptor
12. 0:29and then cause the same physiological
13. 0:32response as the natural ligand or they
14. 0:35can be considered antagonists where they
15. 0:38bind to the receptor don't cause that
16. 0:40physiological response and just block
17. 0:42that receptor and prevent the natural
18. 0:45ligand from going onto that receptor and
19. 0:49just remember as we're talking about
20. 0:50agonists and antagonists in verse
21. 0:52agonists and so forth we're talking
22. 0:54about cellular receptors what can happen
23. 0:57at cellular receptors in two chapters
24. 1:00we're going to be talking about enzymes
25. 1:03and there we talk about enzymatic
26. 1:05Inhibitors so an inhibitor has to do
27. 1:08with enzymes and the agonists and
28. 1:10antagonists always has to do with the
29. 1:13cellular receptor and let's take a
30. 1:16closer look at what happens with our
31. 1:19medications as they bind to a receptor
32. 1:21using the simplest type of cellular
33. 1:24receptor as an example the ligand-gated
34. 1:28Ion channel
35. 1:30recall that the ligands the natural
36. 1:32substance for which the receptor is made
37. 1:35can bind to the receptor because of its
38. 1:39shape but the shape is not the only
39. 1:42factor involved in The Binding it's
40. 1:45really has to do more with the molecular
41. 1:49forces remember that there's various
42. 1:51molecular forces like Van Der waals
43. 1:54forces hydrogen bonding ion bonding all
44. 1:57of those are most important in the
45. 2:00binding and the conformational change
46. 2:04that occurs in order for other things to
47. 2:07happen in that cell
48. 2:09in this example the ligand-gated Ion
49. 2:13channel this portion of the molecule
50. 2:17pulls together opening up a channel and
51. 2:22allowing calcium or other ions from the
52. 2:25outside of the cell to travel through
53. 2:27the channel into the cell
54. 2:30a full Agonist for that receptor is a
55. 2:35substance that does exactly the same as
56. 2:38the natural ligand opening up that gate
57. 2:41to 100 of its capability
58. 2:44notice how in this case that strong ion
59. 2:48Bond was the thing that was responsible
60. 2:51to pull the protein to change the
61. 2:57protein from its original structure to
62. 3:00the new structure and that resulted in
63. 3:03the gate opening what do you think would
64. 3:06happen if a drug shaped the same way
65. 3:10with the same molecular bonds was a
66. 3:14little bit larger maybe just too large
67. 3:18to allow the gate to fully open
68. 3:23in that hypothetical case the molecule
69. 3:26would probably be a partial Agonist
70. 3:30partial agonists don't reach a hundred
71. 3:33percent of the effect that the natural
72. 3:35ligand did even if all of the receptors
73. 3:38are bound now looking at the full
74. 3:41Agonist again what do you think would
75. 3:44happen if you had a drug that was shaped
76. 3:46in the exact same way with the same
77. 3:49attractant Bonds in this corner but you
78. 3:53didn't have that strong ionic bond that
79. 3:57allowed this portion of the protein to
80. 4:01fold up the way that it did with the
81. 4:04normal ligand
82. 4:06in that hypothetical case the drug would
83. 4:10probably be the opposite end of the
84. 4:12spectrum it would have no physiological
85. 4:15effect on the receptor
86. 4:18and it would be termed an antagonist or
87. 4:22sometimes called a blocker
88. 4:25so using the same analogy as the
89. 4:28ion-gated receptor the antagonist may be
90. 4:33exactly the same shape as the natural
91. 4:35ligand or The Agonist but it may be
92. 4:38missing something like the ion bonding
93. 4:41that results in the conformational
94. 4:43change of the protein in this case it
95. 4:47binds to the same spot as the original
96. 4:50ligand but it doesn't open up the gate
97. 4:53that is a competitive antagonist if
98. 4:58there's large amounts of the antagonist
99. 5:00it makes it much less likely that the
100. 5:04ligand is going to bind to that receptor
101. 5:07the final possibility I want to discuss
102. 5:10is an inverse Agonist and this is a bit
103. 5:13more complicated if you want to
104. 5:15simplistically remember what an inverse
105. 5:18Agonist is it's basically an antagonist
106. 5:24with a little bit of an extra benefit
107. 5:26but it'd be good to try to fully
108. 5:29understand what an inverse Agonist is
109. 5:32normally when a receptor is not bound it
110. 5:36is functionally silent nothing is
111. 5:39happening at the receptor the protein is
112. 5:42not causing those flow on effects that
113. 5:45you would normally expect if it was
114. 5:47bound apply this to our ION channel
115. 5:50receptor and when the receptor is not
116. 5:53bound the gate is fully closed no ions
117. 5:57are coming through that channel but some
118. 6:00receptors display what we call a
119. 6:03constitutive activity and that means
120. 6:07that there's a little activity that
121. 6:09occurs just because of the fact that the
122. 6:13receptor protein is there on the cell
123. 6:15surface
124. 6:17this constitutive activity doesn't occur
125. 6:20at every receptor protein and it doesn't
126. 6:23normally occur at this type of receptor
127. 6:26but for simplicity's sake let's continue
128. 6:30using this receptor as the example
129. 6:33an inverse Agonist inhibits that
130. 6:38constitutive activity
131. 6:40so if you want to remember it
132. 6:42simplistically just think of the inverse
133. 6:45Agonist as being an antagonist with some
134. 6:48extra benefits there are some genetic
135. 6:52disorders however that will only respond
136. 6:54to the inverse Agonist
137. 6:56we've just used this simplest cellular
138. 6:59receptor to understand what our
139. 7:01medications can do at cellular receptors
140. 7:04and to further our understanding of
141. 7:06molecular binding of drugs at the
142. 7:09cellular receptors quickly applying our
143. 7:12knowledge to the most common and most
144. 7:14complex cellular receptor the
145. 7:17g-protein-linked receptor and Agonist is
146. 7:20a drug that acts in the same way as the
147. 7:22natural ligand ultimately resulting in
148. 7:26the same cellular response an antagonist
149. 7:30blocks the receptor and that prevents
150. 7:33the natural ligand from binding and
151. 7:36prevents the cellular response it would
152. 7:38occur with ligand binding and an inverse
153. 7:42Agonist would only be possible if the
154. 7:45particular receptor exhibits what we
155. 7:47call some constitutive activity in other
156. 7:50words if that receptor is involved in
157. 7:53some cellular response simply by being
158. 7:56on the cell surface