K+ Pharma

Question 1

Type A blocker

Answer 1

Discrepin 38 aa - TItyus scorpion- Kv4’s

D’suze 2014 cerebellar granular cells

Irreversible

Kinetics not affected

independent of holding potential

Question 2

where does discrepin bind

Answer 2

NTD - affects binding affinity romeo 2018

Question 3

Kv7 blocker

Answer 3

Flurpiritine - PAM of M current

Retigabine - epilepsy - interface of M-channel subunits -stabilizes open limit overall eccitability -> but 2017 discontinued - discolouration of skinmnail ocular tissue

Linopiridine - IM blocker - cognitive enhancer AD - rodent -> shnee and brown 1998

Question 4

Kv1.3 block

Answer 4

Small molcule pap1 - sea anemone toxin based peptide Shk 223

limit amyloid beta plaque burden in mouse models - augmented clearance microglia

Maezuma 2018

Question 5

Kv10.1+10.2 block

Answer 5

Medulloblastoma trailing edge - migration metastasis

thioridazine - Eag2 - slows progression in drosophila and mouse model Huang,2015

Question 6

BK block

Answer 6

Iberiotoxin 37 aa - eastern indian red scorpion

Outer face of BK - high affinity Kd 1 nm - selectively inhbiits

decrease PO and open time - reduce disease severity Rheumatoid arhtritis rats - tanner 2018

DHS-1 legumes - soyaspononin - increase mean open time - asthma urinary incontinence

Question 7

DHS-1 binding stie

Answer 7

4 identical non interacting binding site - 10-20 fold greater affinity to open confomration - binding modifies calcium dependnet and voltge-dep activation

Question 8

SK blocker

Answer 8

Apamin - bee venom - 18 aa - vincent 1975

Tampamin and scyllatoxin - physical block

• compete for same binding site - the pore - Dilly 2011

Question 9

What is apamin used for?

Answer 9

learning and memory rats + mice - but low therapeutic window Faber 2007

Question 10

What salts block SK?

Answer 10

Quaternary ammonium salts

plant -derived bicuculine kawaled 1999
from tubocurarine or dequalinium

Question 11

SK PAMS

Answer 11

EB10 and NS309

Strobaek 2004 - binds at interface between calmodulin and channels - difficult for seletivity due to sequence similarity

Question 12

KATP drugs

Answer 12

1. Diazoxide - hypertension
2. nicrandil - angina
3. cromakalin - lower bp
4. Minoxidil sulfate - KATP opener - TR hypertension

Question 13

Cromakalin actions

Answer 13

Channel opening vasodilator - hyperpolarization - smooth muscle relaxation -> low bp -> kndp in smooth muscle - little effect on blood bglucose umlike diazoxide which acts on pancreatic beta cells

Question 14

What does minoxidil sulfate cause and what does it have to be used with

Answer 14

Rflex tachchardyia + fluid retention - beta blocker and diuretic

Question 15

SUR subunit drugs KATP

Answer 15

Glibenclamide + Tolbutamide - sulfonylureas - - inhibit pancreatic beta cell KATP channels + increase xcell excitability - promote insulin secretion

Question 16

K2P drugs

Answer 16

1. Inhalation GA - halothane - activates TRESK1 and TASK1 K+
2. Unsuual A’s xenon NO cyclopropane - selectively activate TREK1

Question 17

K2P mutations

Answer 17

1. TREK1 - resistance - anti-depressant -> prozac - Lennard 2005 - serotonergic neuron suppression?
2. TRESK - twik related SK - migraine - aura - wood 2010
3. LOF TASK1 - pulmonary hypertension