ANS 10 - drug design p3 - pharmocokinetics

improving pharmacokinetics,properties of agonist ,antagonists

Why is altering pharmacokinetics important?

• Reduce dosing levels

• Improved duration of action

• Better mode of application

What is lipinski’s rule of 5 ?

The ideal characteristics of a drug for oral delivery

If you want it to be orally bioavailable :

• • Molecular weight ≤ 500

  • log P ≤5 - partition coefficient

  • ≤10 H - bond accepting groups

  • ≤5 H - bond donating groups

What combination of molecules are acetylcholine receptors made up from?

• nicotinic, muscarinic

What are some acetylcholine receptors properties /structures ?

• group capable of forming hydrogen bonds

• charged nitrogen forms electrostatic interactions

• ester site

• anionic site

What factors do you need to consider for the receptor interaction site?

• Distance between the two interacting sites

• Substitution pattern on nitrogen

• Substitution at ester

• Chirality (acetylcholine is not but.....)

Why does acetylcholine not have ideal drug characteristics?

• Quaternary ammonium group makes it difficult for the molecule to pass

across the cell membranes

• Ester group is easily hydrolysed by acetylcholine esterase

• Not specific – interacts with all muscarinic and nicotinic receptors

What are the key steps/rules to determine agonist activity in a molecule?

Note - need to be similar to acetylcholine

1. need to have quaternary ammonium - with only one group no bigger than an ethyl

2. Look at the ings rule the distance between the atoms - no more than 5 atoms between the charge and the h atom

3. Does it have an ester /ether - at the right position - 2 carbons away - substituent capable of hydrogen bonding

4. Does it have chirality - if so it needs to be s

What doe sthe length affect ?

 increasing the length between the charge and The last atom decreases activity

 increasing the length between the charge and the last atom decrease s activity

Why is chirality important?

if on the b- carbon increasing potency , increasing selectivity for muscarinic over nicotinic,reduces ester hydrolysis

if on the a- carbon - decrease potency ,increases selectivity for nicotinic

s for - is equipotent with acetylcholine,more active

summary - agonist properties

1. Quaternary ammonium group ESSENTIAL for activity

2. Substitution pattern at nitrogen is CRUCIAL

3. Ings Rule of five

4. Substitution larger than methyl between nitrogen and oxygen reduces activity

5. A substituent capable of HYDROGEN BONDING is ESSENTIAL for binding

What are the properties required for antagonist behaviour ?

• tropane scaffold

• tertiary nitrogen not charged

• etehr for h- bonf formation

• ings rule of 5

Describe the structural properties of an antagonist

• Ideally, nitrogen should be quaternary

• Non quaternary are believed to be protonated by receptor before binding

• Changing substituents to ethyl, isopropyl, etc enables additional positive interactions

• Complex skeleton around nitrogen is not required –

simple alkyl OK

What makes the best antagonists?

• H should be replaced by a carbo or heterocyclic unit

• The best antagonists have one aromatic and one saturated cycle

• Aromatics should not be too large e.g. naphthalene

• Cycles can be fused to give a tricyclic

• The hydroxyl group enables favourable additional H- bonds

What is a binding theory diagram ?

• the squares and circles