MD1: SAR of B-agonists and antimuscarinics

PNS drug targets

Examples of respiratory drugs

Salbutamol mimetic of A/NA binds to B2 receptor

Ipratropium binds to muscarinic receptor

•Short onset, short duration of action bronchodilators.

•Treatment of symptoms of asthma and chronic obstructive

      pulmonary disease (COPD).

•Provide short-term relief.

Explain the 3 stages in SAR

•Start from a lead compound, establish SAR.

•Make specific structural modifications to the lead to convert it into a selective agonist or antagonist, such as…

• Chain extension, conformational restriction, group shifting, chiral switching.

Lead compounds

Prototype chemical structure with desirable biological activity

Found in :

Natural receptor ligands, ACH, NA

Natural products e.g. muscarine

Describe the chemistry functional groups in Ach

Non covalent interactions:

Ester: H-bond interaction

N+ ionic interaction

Describe function of CH3, Ester, Nitrogen

•There is a tight fit between Ach and receptor binding site (little scope for variation).

•Methyl groups fit into small hydrophobic pockets. Van der wall interactions

•Ester interacts by hydrogen bonding (oxygen atoms are potential acceptors).

•Quaternary nitrogen interacts by ionic bonding.

Acetylcholine conformations

Freely rotates around single bond

Large number of possible conformations with varying stability

Binds to different receptors

What are the two types of cholinergic receptors

Nicotinic: activates cholinergic receptors on skeletal muscle

Muscarinic: activates cholinergic receptors on smooth muscle and cardiac muscle

Importance of five membered ring

Ach unable to rotate, locked within a ring, rigid

Restricts the number of possible conformations

Requires separation of the functional groups from the rings

Atropine vs ACH

•Relative positions of ester and nitrogen similar in both molecules.

•Nitrogen in atropine in atropine must be protonated (ionised) when bound to the receptor.

•Amine and ester are important binding groups (ionic + H-bonds).

•Aromatic ring of atropine is an extra binding group (vdW).

•Atropine binds with a different induced fit (larger than Ach) - no activation.

•Atropine binds more strongly than acetylcholine as an antagonist

What is the effect of ionisation

Analogues are fully ionised

unable to cross BBB

avoids systemic side effects

Describe the chemistry of muscarinic receptor antagonists

•Tertiary amine (ionised) or a quaternary nitrogen.

•Aromatic ring.

•Ester.

•N-Alkyl groups (R) can be larger than methyl (unlike agonists).

•Large branched acyl groups allowed (unlike agonists).

•R’ = aromatic or heteroaromatic ring.

•Branching at aromatic/heteroaromatic rings is important

        Þ extra hydrophobic bind regions available next to normal Ach

             binding site??

alpha-adrenoceptors

generally contracts smooth muscle (except gut)

B2 adrenoreceptors

Relaxes smooth muscle

B1 adrenoreceptor

Contracts cardiac muscle

B2 adrenoreceptors

Predominate in the airways

B1 adrenoreceptors

Predominate in the heart

Receptor-selective drugs

act selectively at different organs and tissues

Chemical messengers in adrenergic system

Catecholamines:

Adrenaline: hormone

Noradrenaline: neurotransmitter

Function of catecholamines

Adrenergic agonists, promote the release of chemical from a receptor

Catecholamine chemistry

•Phenol groups form H-bonds to binding site (especially b-adrenoceptors).

•meta-Phenol can be replaced with other hydrogen bonding groups.

•Alcohol forms a hydrogen bond to the binding site (R-enantiomer more active).

•Protonated amine forms an ionic interaction with the binding site.

•N-Alkyl groups affect target selectivity.

•Larger N-alkyl groups lead to selectivity for b-adrenoceptors.

•Aromatic ring forms van der Waals interactions with the binding site.

Breifly describe the adrenergic binding site

Hydrophobic pockets in B-receptors

Isoprenaline B-selectivity

•Shows some selectivity for b-adrenoceptors.

•Bulky isopropyl group introduces b-selectivity

       (chain extension).

•BUT: no selectivity between b-subtypes.

•Cardiovascular side effects (b₁ receptors).

Isoetharine selectivity

•Shows selectivity for b₂-adrenoceptors.

•Ethyl group introduces b₂-selectivity.

•Short lasting due to drug metabolism.

Metabolised by catechol-O-methyltransferase

Salbutamol

B2- selectivety through hydroxymethylene group

Moving phenolic OH prevent metabolism but still has hydrogen bonding

Not cardioselective less side effects

duration of action 2-6h

A racemic mixture but R enantiomer is more active

SABA and SAMA

Ipratropium (SAMA = short-acting muscarinic antagonist)

Salbutamol (SABA = short-acting beta-2 agonist)