L14 Medicinal Chemistry

Adrenaline is ❌-selective for adrenoceptor subtypes and ❌ acting. Drugs designed from adrenaline, noradrenaline as a starting point, were designed with:
– Improved receptor type/subtype ❌
– Longer duration of ❌
– Improved ❌ to metabolism

Catecholamines have a catechol and an amine group.
Catechols (two OH groups adjacent on a ring) are extensively ❌ by COMT (catechol-O methyltransferase), so we can change the catechol to make the drug last ❌.
We can add an extended chain to the amine, which ❌ metabolism by MAO (monoamine oxidase). It can also change molecule structure to ❌ with unique receptor subtype binding pocket shape i.e. we can tune selectivity or ❌ for ARs. Adding an extended lipophilic chain gives ❌ AR selectivity and we can tune the duration of action; the longer the ❌ the longer it stays.

SABAs – Short Acting Beta Agonists, are selective for beta-ARs over alpha-ARs, and more selective for ❌ ARs than ❌ ARs.
They have a fast ❌ of action, and a duration of action ❌ hours, which is longer than endogenous agonists.
– Catechol group no longer there, reduces ❌
– Bulky N-alkyl group, reduces ❌
Most marketed drugs targeting β-AR are a ❌ mixture.

LABAs – Long Acting Beta Agonists, e.g. ❌, have a long chain/lipophilic N-substituent which ❌ with membrane. The drug is ‘anchored’ close to orthosteric ❌ site, giving a longer ❌.
Since LABAs are more lipophilic than SABAs their ❌ is higher.

Beta agonists have an amine that would be ❌ at physiological pH, and therefore are formulated as ❌.
E.g. Terbutaline and salbutamol as sulfate salt, formoterol as fumarate dihydrate salt, salmeterol as the xinafoate salt.
These salts are more ❌ than salts like HCl, and have better ❌ retention.

There are 5 muscarinic GPCR subtypes – M1, M2, M3, M4, M5, also known as ‘muscarinic acetylcholine receptors’ or ‘mAChRs'. The endogenous agonist is ❌ (ACh).
ACh and acts directly at mAChRs on airway ❌ muscle to cause
❌ (in particular via ❌ subtypes). For asthma, bronchodilation can be provided by using an ❌ drug to block effects of ❌ ACh.

SAMAs – Short Acting Muscarinic Antagonists, are ❌ across
M receptor subtypes. They have a quick, ❌ min onset, a duration less than ❌ hours, and provide ❌ relief. An example is ipratropium bromide.
IB systemic exposure is very ❌ due the drug’s physicochemical properties. A permanent ❌ charge limits its diffusion across ❌ and into systemic circulation(this also means it has poor ❌ bioavailability, but when administering to the airways this is not a big problem).

LAMAs, Long Acting Muscarinic Antagonists, are long acting for ❌ reasons. They have very slow ❌ from the M receptor, in particular the M3 subtype. Their clogPs are ❌ to SAMAs and their systemic exposure is limited due to a permanently ❌ charged nitrogen.

Anti-inflammatory drugs are ❌ and act as immunosuppressants, via the ❌. They are often formulated with a ❌.
Structures common to steroids with good activity at the glucocorticoid receptor include:
- ❌ groups (tend to favour GR over MR)
- an ❌ group in a specific position
- a ❌ bond in a specific position
- a ketone
The ketone at carbon number 11 must be ❌ to an alcohol for
glucocorticoid ❌.