Talipexole Hydrochloride

This review discusses the relationship between therapeutic plasma concentrations of antiparkinson dopamine agonists (rotigotine, pergolide, cabergoline, apomorphine, bromocriptine, ropinirole, pramipexole, and talipexole) and their in vitro pharmacology at dopamine D1, D2 and D3 receptors. A significant correlation was found between therapeutic plasma concentrations of these dopamine agonists and their agonist potencies (EC50) at D2 receptors, although no such correlation existed at D1 or D3 receptors, suggesting that D2 receptors could be the primary and common target for the antiparkinson action of all dopamine agonists. However, D1 receptor stimulation is also important for maintaining swallowing reflex, bladder function and cognition. In particular, continuous D1 and D2 receptor stimulation may be reduced to low levels among Parkinson's disease patients. Our findings revealed therapeutic plasma concentrations of rotigotine were similar to its agonist potencies at both D1 and D2 receptors. Thus, rotigotine may be beneficial for the treatment of Parkinson's disease patients in that this dopamine agonist has the potential of continuous stimulation of both D1 and D2 receptors in the clinical setting.

Although G protein-coupled receptors (GPCRs) are traditionally categorized as Gs-, Gq-, or Gi/o-coupled, their signaling is regulated by multiple mechanisms. GPCRs can couple to several effector pathways, having the capacity to interact not only with more than one G protein subtype but also with alternative signaling or effector proteins such as arrestins. Moreover, GPCR ligands can have different efficacies for activating these signaling pathways, a characteristic referred to as biased agonism or functional selectivity. In this work our aim was to detect differences in the ability of various agonists acting at the α2C type of adrenergic receptors (α2C-ARs) to modulate cAMP accumulation, cytoplasmic Ca(2+) release, β-arrestin recruitment and receptor internalization. A detailed comparative pharmacological characterization of G protein-dependent and -independent signaling pathways was carried out using adrenergic agonists (norepinephrine, phenylephrine, brimonidine, BHT-920, oxymetazoline, clonidine, moxonidine, guanabenz) and antagonists (MK912, yohimbine). As initial analysis of agonist Emax and EC50 values suggested possible functional selectivity, ligand bias was quantified by applying the relative activity scale and was compared to that of the endogenous agonist norepinephrine. Values significantly different from 0 between pathways indicated an agonist that promoted different level of activation of diverse effector pathways most likely due to the stabilization of a subtly different receptor conformation from that induced by norepinephrine. Our results showed that a series of agonists acting at the α2C-AR displayed different degree of functional selectivity (bias factors ranging from 1.6 to 36.7) through four signaling pathways. As signaling via these pathways seems to have distinct functional and physiological outcomes, studying all these stages of receptor activation could have further implications for the development of more selective therapeutics with improved efficacy and/or fewer side effects.