Midterm Flashcards
What are the electron donating groups (ED)?
CH3, NH2, OH, OCH3, CH2CH3, O-
What are the electron withdrawing groups?
NO2, NH3+, CN, CF3, X
What groups increase water solubility?
Ionizable groups, N and O
What groups decrease water solubility?
Aromatic groups, alkyl chains and rings (t-butyl, benzene, isopropyl)
How does log P (pi) affect water solubility?
pi>0.5 means lipophilic
pi
Where is aliphatic hydroxylation preferred?
Closer to the middle or on the carbon closest to the aromatic ring
What substituent position do ED groups prefer?
ED groups favour para
How do you decide if a 3 membered ring is cis or trans?
Look at if the groups are sticking out or into the paper.
What happens during N-dealkylation?
The alkyl group on the N is taken off and replaced with an H.
Where is aromatic hydroxylation preferred?
On the para group
What form of a drug is better absorbed?
Unionized
What is the minimum bio availability for oral drugs?
20%
What are Lipinski’s Rule of Fives?
To see if a drug can be absorbed orally:
Molecular weight
How do we want bulky groups in a cyclohexane ring system?
Bulky groups should be equatorial
Any wedge group will be “up”, any dash group will be “down”
What are some examples of non-depolarizing neuromuscular blockers?
d-turbocurarine and pancuronium
What are all neuromuscular blockers used for?
Muscle relaxation during surgery.
What are some examples of depolarizing neuromuscular blockers?
Nicotine, succinylcholine and decamethonium
What are the rules for the structure of a muscarinic agonist?
N+ is required for activity
Removing methyl groups reduces potency
No more than 5 large single bonded atoms long
One eth on R group substitution makes fairly potent, any more decreases
R group longer than 3 C’s can’t fit into receptor
What are some examples of muscarinic agonists? What are they used for?
Edrophonium-diagnostic test for myasthenias gravis
Neostigmine-anesthesia
Pyridostigmine-myasthenia gravis (reversibly alkylates)
Physostigmine-crosses BBB (reversibly alkylates)
How do you stop binding by AchE?
Delocalized electrons
Methyl is added one carbon away from the ring as a steric shield
How do competitive antagonists change the graphs?
Shift dose/response graph to the right. ED50 changes but max efficacy stays the same Affinity decreases (increase in KD)
How do non-competitive antagonists change the graphs?
Shift dose/response graph lower
ED50 stays the same but max efficacy lowers
Affinity stays the same (same KD)
What type of receptor is the epidermal growth factor receptor and what is it needed for?
Transmembrane receptor/enzyme
Needed for growth and differentiation of epithelial cells
How does the epidermal growth factor receptor (EGFR) work?
The receptor is the transmembrane portion, tyrosine kinase is the enzyme. Ligands are epidermal growth factor (EGF) or transforming growth factor alpha (TGFalpha).
The binding of ligands cause cause EGFR dimerization and tyrosine kinase activity, causing autophosphorylation of EGFR tyrosine residues. Causes several signal transduction cascades which results in DNA synthesis and cell proliferation.
How does effector protein G alpha s work?
Binds to adenylate cyclase which makes cAMP which binds to and activates protein kinase A (PKA). PKA then phosphorylates many target proteins and opens Ca channels to pump Ca into the endoplasmic reticulum and increase stores which amplifies the signal again to produce responses.
Phosphodiesterases hydrolyzes cAMP, stopping signal.
How does effector protein G alpha i work?
Inhibits adenylate cyclase and opens K channels (hyperpolarization) causing less excitability
How does effector protein G O work?
Activates receptors that inhibit calcium ion channels leading out of the cell
How does effector protein G alpha q work?
Activates phospholipase C beta (PLCbeta) which hydrolyzes PIP2 to DAG and IP3. Lets Ca into the cell causes adenylate cyclase to make cAMP?
Phosphodiesterases hydrolyze cAMP to shut off
How do depolarizing neuromuscular blocks work?
Will initially depolarize the NMJ like it usually does. But the continued stimulus will cause an increase in resting membrane potential so no muscular contraction is propagated.
How do non-depolarizing neuromuscular blocks work?
Stops the Na channels from opening to depolarize the cell, therefore no muscular contraction is propagated.
What are the requirements of a drug to cross the BBB?
Hydrophobic
Mostly unionized at pH 7.4 (not quaternary amines)
MW
What are some drugs that cross the BBB?
Rivastigmine
Galantamine
Donepezil
Used for alzheimers
What are organophosphate anticholinesterases?
All cross BBB, permanently alkylate the receptor, inactivating it. Increase ACh at the synapse and NMJ
Treated by 2-PAM
What are some examples of organophosphate anticholinesterases?
Sarin (toxic nerve gas)
Malathion and parathion (insecticide)
What are some side effects of organophosphate anticholinesterases?
Bronchospasm, decreased heart rate, profuse sweating, increased GI motility
What are some of the requirements of the structure of muscarinic antagonists?
R1 and R2 should be carbo or heterocyclic. One is aromatic, other is saturated or with 1 double bond.
R3 should be OH, CH2OH
X should be an ester
N should be a quaternary ammonium or tertiary amine (must have + charge)
The distance between the ring and N is usually 2-4 carbons long
What are some examples of muscarinic antagonists?
Oxybutynin and Tolerodine-overactive bladder
Benztropine-Counteracts parkinson’s like symptoms from schizophrenia treatment
Scopolamine-motion sickness
Hyoscine-GI spasms
Ipratropium and Tiotropium-COPD
What is a requirement for sympathomimetic agonists?
OH in the m and beta position
As the size of the R substituent increases, intrinsic activity decreases but affinity increases.
What is a requirement for sympathomimetics with amphetamine activity?
No OH in m and beta position.
What does MAO do?
Removes N to eliminate activity
What does COMT do?
Adds a methyl group in the meta position, which reduces activity
What are the main metabolites of NA and A?
MOPEG and VMA, conjugated before excretion
How does amphetamine work?
Causes the release of NA, dopamine and serotonin from the presynaptic vesicles by binding to and inhibiting MAO. This increases [MA] and blocking VMAT2 which takes MA up into vesicles.
Amphetamine is taken up by the same transporter that takes up NA, dopamine and serotonin and thus competes for the transporter, leaving increased levels of the 3 in the synapse. The vesicular concentrations are so high that the transporter pump works backwards and pumps MA, serotonin, NA and dopamine into the synapse
How does cocaine work?
Stops the reuptake of serotonin, NA and dopmine by transporters from the synapse.
What makes a drug selective for alpha 2 receptors?
Guanidine group Central NH Two ortho substituents N substitution is smaller than isopropyl Methyl in alpha position
What are some examples of alpha 2 agonists?
Clonidine (menopause)
Methyldopa (hypertension during pregnancy)
Pseudophedrine (mixed with alpha 1)
What makes a drug selective for alpha 1 receptors?
Presence of imidazole
Meta and para substitution
Hydrophobic substitutions
What are some examples of alpha 1 agonists?
Imidazoline
Phenylephrine
Pseudophedrine (mixed with alpha 2)
What makes a good beta agonist?
secondary amine or pheylethylamines
As R increases, affinity increases while intrinsic activity increases or stays the same
2 substitutions on the aromatic ring capable of H-bonds
What makes a drug selective for beta 1 receptors?
Isopropyl R substituent
What makes a drug selective for beta 2 receptors?
t-butyl R substituent OH in beta position Resorcinol ring Hydrophobic 7-11 carbon long chains Distance between NH and rings are 3 not 2 carbons
What are some examples of beta 1 agonists?
Isoproterenol (mixed with beta 2)
Dobutamine
What are some examples of beta 2 agonists?
Isoproterenol (mixed with beta 1)
Salbutamol and Terbutaline (short acting for COPD and asthma attack)
Indacterol (long acting for COPD and asthma control)
What are some side effects of beta 2 agonists?
Muscle tremors, increased heart rate
How do you reduce metabolism by MAO?
t-butyl N substitution
Methyl alpha substitution
How do you reduce metabolism by COMT?
OH in para position
Meta substitutions are helpful (hydroxyethyl, N-formyl, sulfonamide, resorcinol derivatives)
What are some structure requirements for alpha antagonists?
N must be charged
R1 and R2 must be CH3 or t-butyl and larger
Distance between X and N can be 1-3 carbons
What are some non-selective alpha antagonists?
Phenoxybenzamine (irreversible-alkylated)
Phentolamine
What is normal blood pressure?
120/80
What blood pressure is considered a hypertensive crisis?
> 180/>110
How can we decrease TPR?
Block alpha 1 receptors to cause vasconstriction
Produce NO using hydrochlorothiazide
Ca channel blockers (Nifedipine, amlodipine)
How can we decrease CO?
Block beta 1 receptor to prevent a heart rate increase
Ca channel blockers (verapramil, diltiazem)
What are some examples of selective alpha antagonists?
Alpha 1
Prazosin
Terazosin
Doxazosin
All above are used to decrease blood pressure without increasing heart rate
Tamsulosin (BPH due to alpha 1A selectivity)
What are some side effects of selective alpha antagonists?
Postural hypotension
Syncope
What is the starting dose of quinzolines?
1 mg at night. Dose is then titrated to blood pressure
