The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human β1- and β3-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both β1- and β3-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both β1- and β3-AR. The 3′,5′-diiodo-4′-amino analog of TMQ was the most potent β3-AR agonist, 17-fold more potent at the β3-AR versus the β1-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3′,5′-diiodo-4′-acetamido analog of TMQ, a potent β1- and β3-AR agonist, abolished activity at both β-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at β1- and β3-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at β1- and β3-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of β1- and β3-AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent β3-AR agonists.

Keywords:
β-Adrenergic receptor, Trimetoquinol, Structure-activity relationship, β-Agonist
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© 2001 S. Karger AG, Basel
2001
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