β-blockers' binding site to the receptor is the same as for endogenous catecholamines, such as noradrenaline and adrenaline. This binding is based on hydrogen bonds between the β-blocker and the receptor, and therefore not based on covalent bonds, which results in the reversibility of the binding. A significant step in the development of β adrenergic antagonists was the discovery that an oxymethylene bridge (—OCH—, figure 7) could be inserted into the arylethanolamine structure of pronethalol to produce propranolol. Propranolol is an aryloxypropanolamine, which are more potent β-blockers than arylethanolamines. Today, most of the β-blockers used clinically are aryloxypropanolamines. The length of the side chain is increased when an oxymethylene bridge is introduced. It has been shown that the side chains of aryloxypropanolamine can adopt a conformation that puts the hydroxyl and amine groups in more or less the same position as with beta blocker that do not have this group as a part of the side chain.
After the release of propranolol, relative lipophilicity of β-blockers as a significant factor in their varied and complex pharmacology, became an important factor. It was suspected that propranolols centrally induced side effects could be due to its high lipophilicity. Thus, it was focused on synthesizing analogues with hydrophilic moieties, favourably placed to see if the side effects would decrease. Selecting para-acylamino groups as the hydrophilic moiety, scientists synthesized a group of para-acylphenoxyethanol and propanolamines, and selected practolol for clinical trials. Practolol had one property not previously seen with β-blockers, it exhibited cardioselectivity (β selectivity). Studies from practolol showed that moving the acylamino group to meta or ortho positions, on the benzene ring, caused a loss of selectivity but not loss of the β-blockade itself. This illustrated the significance of para'-substitution for β selectivity of β-blockers.
Figure 8 shows the structure-activity relationship (SAR) for β-blockers. For the function of a β-blocker it's essential for the compound to contain an aromatic ring and a β-ethanolamine. The aromatic ring can either be benzoheterocyclic (such as indole) or heterocyclic (such as thiadiazole). This is mandatory. The side chains can be variable:
* The X part of the side chain can either be directly linked to the aromatic ring or linked through a —OCH— group
* When X is —CHCH—, —CH=CH—, —SCH— or —NCH—, there is little or no activity
* The R group can only be a secondary substitution and branched is the optimal choice
* Alkyl (—CH) substituents on the α, β or γ carbon (if X = —OCH—) lower beta blockade, especially at the α carbon
The general rule for aromatic substitution is: ortho > meta > para. This gives non-selective β-blockers. Large para-substituents usually decrease activity but large ortho-groups retain some activity. Polysubstitution on carbon 2 and 6 makes the compound inactive but when the substitution is on carbon 3 and 5 theres some activity. For the highest cardioselectivity, the substituents should be as following: para > meta > ortho. All the β-blockade is in one isomer, (S)-aryloxypropylamine and (R')-ethanolamine.