Selectivity of the imidazoline α‐adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned α₁‐adrenoceptor subtypes

Abstract

1. To investigate the structure-activity relationships of alpha-adrenoceptor agonists for the alpha 1-adrenoceptor subtypes, we have compared the imidazoline class of compounds, oxymetazoline and cirazoline, with the phenethylamine, noradrenaline, in their affinities and also in their intrinsic activities in Chinese hamster ovary (CHO) cells stably expressing the cloned human alpha 1-adrenoceptor subtypes (alpha 1a-, alpha 1b-, and alpha 1d-subtypes). 2. Radioligand binding studies with [125I]-HEAT showed that cirazoline and oxymetazoline had higher affinities at alpha 1a-subtype than at alpha 1b- and alpha 1d-subtypes, while noradrenaline had higher affinity at the alpha 1d-subtype than at alpha 1a- and alpha 1b-subtypes. 3. In functional studies, cirazoline caused transients of cytosolic Ca2+ concentrations ([Ca2+]i response) in a concentration-dependent manner and developed a maximal response similar to that to noradrenaline in CHO cells expressing the alpha 1a-subtype, while it acted as a partial agonist at alpha 1b- and alpha 1d-adrenoceptors. Oxymetazoline, on the other hand, was a weak agonist at alpha 1a-adrenoceptors, and has no intrinsic activity at the other subtypes. 4. Using the phenoxybenzamine inactivation method, the relationships between receptor occupancy and noradrenaline-induced [Ca2+]i response for alpha 1a- and alpha 1d-subtypes were found to be linear, whereas it was moderately hyperbolic for the alpha 1b-subtype, indicating the absence of receptor reserves in CHO cells expressing alpha 1a- and alpha 1d-subtypes while there exists a small receptor reserve for CHO cells expressing the alpha 1b-subtype. 5 In summary, our data obtained in cells exclusively expressing a single receptor subtype support the idea that the relative role of agonist affinity and intrinsic activity may vary depending on the subtype of alphal-adrenoceptor.

Signal Transduction Pathways Associated with α₁-Adrenoceptor Subtypes in Cells and Tissues Including Human Prostate

“…cirazoline and oxymetazoline) were functionally selective for the α 1a -subtype. This finding was supported using Chinese hamster ovary (CHO) cells stably expressing either the α 1a - or the α 1b - or the α 1d -subtype and measuring cytosolic Ca 2+ concentrations [15]. While noradrenaline was an effective agonist at raising [Ca 2+ ] i in all cell lines, cirazoline had a similar maximum response only in those cells expressing the α 1a -subtype, being a partial agonist at the other two receptors.…”

L-765,314 Suppresses Melanin Synthesis by Regulating Tyrosinase Activity

“…Having observed the expression of ADRA1b, we then considered whether the suppression of melanin production by L-765,314 was mediated by inhibition of adrenoceptors and, conversely, whether the activation of adrenoceptors, or, more specifically, ADRA1b, may enhance melanin production. However, neither exposure to phenylephrine, a selective ADRA agonist [ 8 , 9 ], nor to cirazoline, a full ADRA1a agonist and partial agonist for ADRA1b and ADRA1b [ 10 , 11 ], increased the melanin content in Mel-ab cells ( Figure 4 B,C and Figure S2 ).…”

Ligands of Adrenergic Receptors: A Structural Point of View

“…In this review, we summarized current achievements of structural study in adrenergic receptors and advances in drug discovery based on these structures. [12][13][14] of endogenous agonists in the nine adrenergic receptors. (b) Number of new drugs (approved or first marketing) for the nine adrenergic receptors in each decade.…”

“…Adrenergic receptors as drug targets. (a) Binding affinities[12][13][14] of endogenous agonists in the nine adrenergic…”