A series of derivatives structurally related to biphenyline (3) was designed with the aim to modulate selectivity toward the alpha(2)-AR subtypes. The results obtained demonstrated that the presence of a correctly oriented function with positive electronic effect (+sigma) in portion X of the ligands is an important factor for significant alpha(2C)-subtype selectivity (imidazolines 5, 13, 16, and 19). Homology modeling and docking studies support experimental data and highlight the crucial role for the hydrogen bond between the pyridine nitrogen in position 3 of 5 and the NH-indole ring of Trp6.48, which is favorably oriented in the alpha(2C)-subtype, only.

SYNOPSIS Duchenne muscular dystrophy (DMD) is an incurable, rapidly-worsening neuromuscular degenerative disease caused by the absence of dystrophin. In skeletal muscle, lack of dystrophin disrupts the recruitment of neuronal nitric oxide synthase (nNOS) to the sarcolemma thus affecting nitric oxide (NO) production. Utrophin is a dystrophin homolog which expression is greatly upregulated in the sarcolemma of dystrophin-negative fibers from mdx mice, a mouse model of DMD. Although cardiomyopathy is an important cause of death, little is known about the NO signaling pathway in cardiac muscle of DMD patients. Thus, we used cardiomyocytes and hearts from two month-old mdx and mdx:utrophin (−/−) double knockout mice (mdx:utr) to study key steps in NO signaling: L-arginine transporters, NOS, and soluble guanylyl cyclase (sGC). nNOS did not co-localize with dystrophin or utrophin to the cardiomyocyte membrane. Despite this, nNOS activity was markedly decreased in both mdx and mdx:utr mice while nNOS expression was only decreased in mdx:utr hearts, suggesting that utrophin upregulation in cardiomyocytes maintains nNOS levels but not function. sGC protein levels and activity remained at control levels. Unexpectedly, L-arginine transporter expression and function were significantly increased, suggesting a novel biochemical compensatory mechanism of the NO pathway and a potential entry site for therapeutics.

The family of alpha(2)-adrenergic receptors (alpha(2)-ARs) comprises three subtypes which are each endowed with specific functions. alpha(2)-agonists and alpha(2)-antagonists are part of the clinician armamentarium since several decades; however, none of the compounds so far available is subtype selective. For long, clonidine and yohimbine have been used for the treatment of hypertension and impotence respectively, but both have been superseded by newer drugs. This review attempts, by a comprehensive analysis of the literature, to cover the present clinical use and the potential therapeutic interest of alpha(2)-agonists or antagonists. From the clinical data, it is concluded that, with the exception of a few particular situations, alpha(2)-agonists are only of limited utility as a monotherapy. By contrast, they offer several powerful advantages when used in adjunctive therapy. In perioperative settings, alpha(2)-agonists are extremely valuable adjuncts to anesthetics and analgesics for the induction of anxiolysis, maintenance of sedation, management of pain and prevention of shivering. In the ophthalmic clinic, they are used to lower intra-ocular pressure during laser surgery of the eye. As a daily medication, alpha(2)-agonists are also of interest for the treatment of glaucoma, muscle spasticity, opiate withdrawal, and behavior disorders. The alpha(2)-antagonists are useful antidotes for reversing the threatening effects of agonist overdose, but currently there are very few indications. New applications are under investigation, and new molecules with more refined subtype-selectivity may emerge, so the clinical utility of both alpha(2)-agonists and antagonists will undoubtedly expand in the future.

To assess the stereochemical requirements for efficient alpha2C-adrenoreceptor activation, the enantiomeric forms of m-nitrobiphenyline [(+/-)-5] were prepared and tested on cells expressing the human alpha2-adrenoreceptor subtypes. The importance of chirality was confirmed, since the enantiomer (R)-(+)-5 was much more efficient than (S)-(-)-5 in producing alpha2C-activation. Surprising reversal of enantioselectivity was observed with respect to structurally similar biphenyline [(+/-)-1] whose (S)-(-)-form proved the preferred alpha2C-configuration.