Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.

Article Details

Citation

Copy to clipboard

Perrone MG, Santandrea E, Bleve L, Vitale P, Colabufo NA, Jockers R, Milazzo FM, Sciarroni AF, Scilimati A

Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.

Bioorg Med Chem. 2008 Mar 1;16(5):2473-88. Epub 2007 Nov 28.

PubMed ID

18083578 [ View in PubMed

]

Abstract

Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Isoprenaline	Beta-3 adrenergic receptor	EC 50 (nM)	5.8	N/A	N/A	Details
Isoprenaline	Beta-3 adrenergic receptor	EC 50 (nM)	3.9	N/A	N/A	Details
Norepinephrine	Beta-3 adrenergic receptor	EC 50 (nM)	5.5	N/A	N/A	Details
Norepinephrine	Beta-3 adrenergic receptor	EC 50 (nM)	6.3	N/A	N/A	Details