Block C Lecture 3 - Complex Pharmacology of Free Fatty Acid Receptors Flashcards
What is a carboxylic acid?
An organic compound that contain at least one carboxyl group (-COOH)
(Slide 4)
What is a fatty acid?
A carboxylic acid linked to an aliphatic tail (a hydrocarbon tail of varying length)
(Slide 4)
What are the 3 categories of fatty acids based on size?
Short chain fatty acids (SCFA) - 6 or less carbon chain
Medium chain fatty acids (MCFA) - 7-12 carbon chain
Long chain fatty acids (LCFA) - > 13 carbon chain
(Slide 4)
What are the 3 classifications of fatty acids based on saturation?
Saturated fatty acids (SFA) - fatty acids with no double bonds in them
Monounsaturated (MUFA) - fatty acids with one double bond in them
Polyunsaturated (PUFA) - contain more than one double bond
(Slide 4)
Where are medium and long chain fatty acids obtained from and synthesised in?
They are obtained from dietary fat but can also be synthesised de novo (from scratch) in the liver
(Slide 5)
What are essential fatty acids?
A group of polyunsaturated fatty acids (PUFAs) that must be obtained from the diet
(Slide 5)
What do essential fatty acids help synthesise?
Polyunsaturated fatty acids
(Slide 5)
What 2 signalling molecules are medium and long chain fatty acids precursors for?
Prostaglandins and leukotrienes
(Slide 5)
When are short chain fatty acids produced?
When dietary fibre is fermented in the colon by microbiota of the gut
(Slide 5)
What are the four family members of FFA GPCRs?
FFA1
FFA2
FFA3
FFA4
(creative I know)
(Side 6)
What 2 FFA receptors do short chain fatty acids target?
FFA2 and 3 receptors
(Slide 6)
What 2 FFA receptors do medium and long chain fatty acids target?
FFA1 and 4 receptors
(Slide 6)
What cells are FFA2Rs expressed in and what is their function?
Immune cells - Act as neutrophil chemotaxis
Enteroendocrine cells - Gut hormone secretion
Adipocytes - Inhibition of Lipolysis
Pancreatic β-cells - regulation of insulin secretion
(Slide 7)
What are cells FFA3Rs expressed in and what is their function?
Enteroendocrine cells - gut hormone secretion
Pancreatic β-cells - inhibition of insulin secretion
Sympathetic ganglia (unknown function)
(Slide 7)
What are cells FFA4Rs expressed in and what is their function?
Enteroendocrine cells - gut hormone secretion
Adipocytes - stimulate glucose uptake
Immune cells - Inhibit cytokine secretion
Pancreas islets - Regulation of hormone secretion
(Slide 7)
What has knowing the crystal structure of FFA1R allowed us to do?
Gain knowledge of the regions of ligand binding, and allowing us to design and develop new drugs based on this information
(Slide 8)
What are 4 examples of where FFA1Rs are found and what are their functions in these different locations?
CNS - Modulates cognitive defects, chronic pain, emotional and maternal behaviour, epileptic seizures, reduction of energy efficiency and regulation of inflammation
Taste buds - taste perception
Pancreatic β-cells - insulin secretion
Enteroendocrine I, K, L - CCK, GIP and GLP-1 secretion (regulate digestion, metabolism and appetite)
Osteoclast and Osteoblast cells (in the bone) - Inhibition of osteoclastogenesis (formation of osteoclasts) and stimulation of bone formation
Bone-marrow-derived cells - induction of differentiation of M2 macrophages
(Slide 16)
What fatty acids have the highest potency in activating the FFA1R?
Long chain poly-unsaturated fatty acids
(Slide 18)
What fatty acids are considered poor agonists for the FFA1R?
Trans-unsaturated fatty acids
(Slide 18)
What does acute long chain fatty acids treatment result in?
Enhanced - glucose-dependent insulin secretion (GSIS)
(Slide 18)
What does chronic long chain fatty acid treatment result in?
Lipotoxicity and inhibition of insulin secretion
(Slide 18)
What are 2 examples of endogenous FFA1R agonists?
α-linolenic acid (ALA)
Docosahexaenoic acid (DHA)
(Slide 19)
What is TAK875 (Fasiglifam)?
A drug that acts as a FFA1 agonist, activating Arrestin 2/3 pathways
(Slide 20)
What activity is reduced in Arrestin KO mice?
Insulintropic (the ability of the body to secrete insulin) activity
(Slide 20)
What pathway do long chain fatty acids activate when they bind to FFA1 receptors?
Gq protein pathway
(Slide 20)
What does inhibition of Gq lead to?
Insulintropic activity being ablated (completed eliminated)
(Slide 20)
What are the properties of AM1638, especially when compared to TAK875 (Fasiglifam)?
It is a full agonist, which has a distinct binding profile from TAK, and has better preclinical data; being more effective in regulating blood glucose insulin levels, an showing effects with GLP-1, GIP and insulin levels which TAK doesn’t.
It transduces Gs and Gq pathways, meaning it activates them both
(Slide 20)
What are glitazones?
FFA1 agonists, which are used as anti-diabetic drugs. Examples include:
Rosiglitazone
Netoglitazone
Troglitazone
(Slide 22)
Why have studies investing the possibility of synthetic ligands for FFA2 receptors been hampered?
As they’ve only done rodent based studies so far and there is no guarantee they’ll work the same in humans
(Slide 23)
Why are scientists pursuing FFA2 agonism?
To limit obesity
(Slide 23)
Why have FFA2 antagonism studies using GLPG0974 been pursued and why did they fail?
For protection against ulcerative colitis, a chronic inflammatory disease that causes inflammation and ulcers in the colon and rectum. The drug failed as it showed no clinical benefit over a placebo
(Slide 23)
What issues have scientists had developing FFA3 allosteric agonists?
Potency issues
(Slide 23)
What is the problem with developing orthosteric agonists for FFA4Rs?
Spice variant genetic polymorphisms. There is a 3% polymorphism in the European cohort where the receptor loses the ability to couple with G proteins but can still activate the Arrestin 2/3 pathway.
(Slide 23)
What studies can provide insight into FFA4Rs feasibility as a drug target?
Population studies (to determine how many variants there are and if they act differently, if they influence disease risk etc)
(Slide 23)
