1-Benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diols as novel affinity and photoaffinity probes for β-adrenoceptor subtypes

• Published in: Bioorganic & medicinal chemistry 2006-03, Vol.14 (6), p.1684-1697
• Main Authors: Nikulin, Victor I., Rakov, Igor M., De Los Angeles, Joseph E., Mehta, Ratna C., Boyd, LeNe’Sheya Y., Feller, Dennis R., Miller, Duane D.
• Format: Article
• Language: English
• Subjects: 1,2,3,4-Tetrahydroisoquinoline; Adrenergic beta-Agonists - chemistry; Agonist; Animals; Biological and medical sciences; Catecholaminergic system; Cells, Cultured; Cricetinae; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Photoaffinity Labels - chemical synthesis; Photoaffinity Labels - chemistry; Photoaffinity probe; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta - physiology; Tretoquinol - analogs & derivatives; Tretoquinol - chemistry; β 3-Adrenergic receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.12.027

Trimetoquinol (TMQ, 1) is a potent non-selective β-adrenoceptor (β-AR) agonist possessing a tetrahydroisoquinoline (THI) structure. The binding site for 1-trimethoxybenzyl group of 1, which distinguishes it from classical catecholamines, is unknown. Affinity and photoaffinity labeled compounds are good tools to determine the exact interaction between a ligand and a specific amino acid(s) in a receptor. In this study, we designed and synthesized a series of affinity 6, 12, 18, and photoaffinity 24, 29 labeled analogues of TMQ. All of these compounds were full agonists and demonstrated an equal or greater binding affinity and functional activity as compared to TMQ on β 1-, β 2-, and β 3-AR. Washout experiments on Chinese hamster ovary (CHO) cells expressing hu β 2-AR were helpful in identifying the isothiocyanate 18 and the azide 24 as very effective affinity and photoaffinity labels at this receptor subtype.