Effect of the rigidification of propranolol, a mixed β-adrenoceptor and 5-HT_1AR antagonist

Propranolol is a popular β adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT_1A/B. In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at β-adrenoreceptors and 5-HT_1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at β_1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT_1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT_1AR activity.