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BM324: Fundamental Pharmacology > Block C Lecture 3 - Complex Pharmacology of Free Fatty Acid Receptors > Flashcards

Block C Lecture 3 - Complex Pharmacology of Free Fatty Acid Receptors Flashcards

1
Q

What is a carboxylic acid?

A

An organic compound that contain at least one carboxyl group (-COOH)

(Slide 4)

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2
Q

What is a fatty acid?

A

A carboxylic acid linked to an aliphatic tail (a hydrocarbon tail of varying length)

(Slide 4)

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3
Q

What are the 3 categories of fatty acids based on size?

A

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)

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4
Q

What are the 3 classifications of fatty acids based on saturation?

A

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)

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5
Q

Where are medium and long chain fatty acids obtained from and synthesised in?

A

They are obtained from dietary fat but can also be synthesised de novo (from scratch) in the liver

(Slide 5)

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6
Q

What are essential fatty acids?

A

A group of polyunsaturated fatty acids (PUFAs) that must be obtained from the diet

(Slide 5)

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7
Q

What do essential fatty acids help synthesise?

A

Polyunsaturated fatty acids

(Slide 5)

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8
Q

What 2 signalling molecules are medium and long chain fatty acids precursors for?

A

Prostaglandins and leukotrienes

(Slide 5)

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9
Q

When are short chain fatty acids produced?

A

When dietary fibre is fermented in the colon by microbiota of the gut

(Slide 5)

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10
Q

What are the four family members of FFA GPCRs?

A

FFA1
FFA2
FFA3
FFA4
(creative I know)

(Side 6)

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11
Q

What 2 FFA receptors do short chain fatty acids target?

A

FFA2 and 3 receptors

(Slide 6)

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12
Q

What 2 FFA receptors do medium and long chain fatty acids target?

A

FFA1 and 4 receptors

(Slide 6)

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13
Q

What cells are FFA2Rs expressed in and what is their function?

A

Immune cells - Act as neutrophil chemotaxis

Enteroendocrine cells - Gut hormone secretion

Adipocytes - Inhibition of Lipolysis

Pancreatic β-cells - regulation of insulin secretion

(Slide 7)

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14
Q

What are cells FFA3Rs expressed in and what is their function?

A

Enteroendocrine cells - gut hormone secretion

Pancreatic β-cells - inhibition of insulin secretion

Sympathetic ganglia (unknown function)

(Slide 7)

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15
Q

What are cells FFA4Rs expressed in and what is their function?

A

Enteroendocrine cells - gut hormone secretion

Adipocytes - stimulate glucose uptake

Immune cells - Inhibit cytokine secretion

Pancreas islets - Regulation of hormone secretion

(Slide 7)

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16
Q

What has knowing the crystal structure of FFA1R allowed us to do?

A

Gain knowledge of the regions of ligand binding, and allowing us to design and develop new drugs based on this information

(Slide 8)

17
Q

What are 4 examples of where FFA1Rs are found and what are their functions in these different locations?

A

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)

18
Q

What fatty acids have the highest potency in activating the FFA1R?

A

Long chain poly-unsaturated fatty acids

(Slide 18)

19
Q

What fatty acids are considered poor agonists for the FFA1R?

A

Trans-unsaturated fatty acids

(Slide 18)

20
Q

What does acute long chain fatty acids treatment result in?

A

Enhanced - glucose-dependent insulin secretion (GSIS)

(Slide 18)

21
Q

What does chronic long chain fatty acid treatment result in?

A

Lipotoxicity and inhibition of insulin secretion

(Slide 18)

22
Q

What are 2 examples of endogenous FFA1R agonists?

A

α-linolenic acid (ALA)
Docosahexaenoic acid (DHA)

(Slide 19)

23
Q

What is TAK875 (Fasiglifam)?

A

A drug that acts as a FFA1 agonist, activating Arrestin 2/3 pathways

(Slide 20)

24
Q

What activity is reduced in Arrestin KO mice?

A

Insulintropic (the ability of the body to secrete insulin) activity

(Slide 20)

25
Q

What pathway do long chain fatty acids activate when they bind to FFA1 receptors?

A

Gq protein pathway

(Slide 20)

26
Q

What does inhibition of Gq lead to?

A

Insulintropic activity being ablated (completed eliminated)

(Slide 20)

27
Q

What are the properties of AM1638, especially when compared to TAK875 (Fasiglifam)?

A

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)

28
Q

What are glitazones?

A

FFA1 agonists, which are used as anti-diabetic drugs. Examples include:
Rosiglitazone
Netoglitazone
Troglitazone

(Slide 22)

29
Q

Why have studies investing the possibility of synthetic ligands for FFA2 receptors been hampered?

A

As they’ve only done rodent based studies so far and there is no guarantee they’ll work the same in humans

(Slide 23)

30
Q

Why are scientists pursuing FFA2 agonism?

A

To limit obesity

(Slide 23)

31
Q

Why have FFA2 antagonism studies using GLPG0974 been pursued and why did they fail?

A

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)

32
Q

What issues have scientists had developing FFA3 allosteric agonists?

A

Potency issues

(Slide 23)

33
Q

What is the problem with developing orthosteric agonists for FFA4Rs?

A

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)

34
Q

What studies can provide insight into FFA4Rs feasibility as a drug target?

A

Population studies (to determine how many variants there are and if they act differently, if they influence disease risk etc)

(Slide 23)

BM324: Fundamental Pharmacology (15 decks)

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