L14 Medicinal Chemistry

“Nor” means desmethyl/minus a methyl group, so noradrenaline is structurally the same as the catecholamine adrenaline, without a methyl group.

Adrenaline is [blank_start]non[blank_end]-selective for adrenoceptor subtypes and [blank_start]short[blank_end] acting. Drugs designed from adrenaline, noradrenaline as a starting point, were designed with: – Improved receptor type/subtype [blank_start]selectivity[blank_end] – Longer duration of [blank_start]action[blank_end] – Improved [blank_start]stability[blank_end] to metabolism

Catecholamines have a catechol and an amine group. Catechols (two OH groups adjacent on a ring) are extensively [blank_start]metabolised[blank_end] by COMT (catechol-O methyltransferase), so we can change the catechol to make the drug last [blank_start]longer[blank_end]. We can add an extended chain to the amine, which [blank_start]reduces[blank_end] metabolism by MAO (monoamine oxidase). It can also change molecule structure to [blank_start]match[blank_end] with unique receptor subtype binding pocket shape i.e. we can tune selectivity or [blank_start]affinity[blank_end] for ARs. Adding an extended lipophilic chain gives [blank_start]beta 2[blank_end] AR selectivity and we can tune the duration of action; the longer the [blank_start]lipophilic chain[blank_end] the longer it stays.

SABAs – Short Acting Beta Agonists, are selective for beta-ARs over alpha-ARs, and more selective for [blank_start]beta 2[blank_end] ARs than [blank_start]beta 1[blank_end] ARs. They have a fast [blank_start]onset[blank_end] of action, and a duration of action [blank_start]4-6[blank_end] hours, which is longer than endogenous agonists. – Catechol group no longer there, reduces [blank_start]COMT metabolism[blank_end] – Bulky N-alkyl group, reduces [blank_start]MAO metabolism[blank_end] Most marketed drugs targeting β-AR are a [blank_start]racemic[blank_end] mixture.

LABAs – Long Acting Beta Agonists, e.g. [blank_start]salmeterol[blank_end], have a long chain/lipophilic N-substituent which [blank_start]associates[blank_end] with membrane. The drug is ‘anchored’ close to orthosteric [blank_start]binding[blank_end] site, giving a longer [blank_start]duration of action[blank_end]. Since LABAs are more lipophilic than SABAs their [blank_start]clogP[blank_end] is higher.

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

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

Atropine is a typical antimuscarinic, but is not selective and has side effects.

SAMAs – Short Acting Muscarinic Antagonists, are [blank_start]non-selective[blank_end] across M receptor subtypes. They have a quick, [blank_start]15[blank_end] min onset, a duration less than [blank_start]4[blank_end] hours, and provide [blank_start]short term[blank_end] relief. An example is ipratropium bromide. IB systemic exposure is very [blank_start]limited[blank_end] due the drug’s physicochemical properties. A permanent [blank_start]positive[blank_end] charge limits its diffusion across [blank_start]membranes[blank_end] and into systemic circulation(this also means it has poor [blank_start]oral[blank_end] bioavailability, but when administering to the airways this is not a big problem).

LAMAs, Long Acting Muscarinic Antagonists, are long acting for [blank_start]kinetic[blank_end] reasons. They have very slow [blank_start]off binding[blank_end] from the M receptor, in particular the M3 subtype. Their clogPs are [blank_start]similar[blank_end] to SAMAs and their systemic exposure is limited due to a permanently [blank_start]positively[blank_end] charged nitrogen.

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