hydrogen bonds to two serine residues within the active site and the cationic amine nitrogen forms an ionic bond with a negatively charged aspartic acid residue at the active site. The β-OH group also participates in a critical hydrogen bond with an asparagine residue at the active site of the receptor. It has nonselective adrenergic activity because the small methyl group on the nitrogen allows access to both α and β adrenergic receptors. I didn’t mention it in class, but this drug only acts peripherally because the catechol group is too polar and prevents it from crossing the BBB.
Compound 2 has the aryloxypropanolamine backbone; therefore, you know that it has β-adrenergic antagonist (β-blocker) activity. It has no α-adrenergic activity due to the t-butyl group on the nitrogen which does not allow access to α-adrenergic receptors. It binds to β-receptors slightly differently than an agonist; therefore, it has affinity to β-receptors, but it does not have intrinsic activity. It does not possess a substituent at the 4 position ( para -position) of the aryl ring; therefore, this compound is a nonselective β-adrenergic antagonist which means it will have antagonist activity at both β 1 and β 2 -adrenergic receptors. This compound is polar due to the two hydroxyl groups on the ring system and has one of the lower partition coefficients (cLogP = 1.3) of the β-blockers. Due to its lower lipophilicity, it is excreted by the kidney unchanged.
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- Spring '14