A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066

Area of Science:

• Pharmacology
• Neuroscience
• Adrenoceptor Antagonism

Background:

• Alpha-2 adrenoceptors play crucial roles in both central and peripheral nervous systems.
• Selective antagonists are valuable tools for dissecting adrenoceptor function.
• L-657,743 is a known alpha-2 adrenoceptor antagonist.

Purpose of the Study:

• To characterize the novel alpha-2 adrenoceptor antagonist L-659,066.
• To compare its potency and selectivity with L-657,743.
• To assess its ability to penetrate the blood-brain barrier.

Main Methods:

• In vitro assays: pA2 determination at alpha-2 adrenoceptors (rat vas deferens), radioligand binding assays ([3H]rauwolscine, rat cerebrocortical membranes).
• In vivo studies: Pithed rat model (peripheral receptor blockade), rat models for central nervous system effects (dopa accumulation, clonidine-induced mydriasis antagonism).
• Mouse model for peripheral and central effects of clonidine and UK 14,304.

Main Results:

• L-659,066 is a potent and selective alpha-2 adrenoceptor antagonist, comparable to rauwolscine in selectivity over alpha-1 adrenoceptors.
• In vitro and in vivo, L-659,066 demonstrated lower potency than L-657,743 at both peripheral and central alpha-2 adrenoceptors.
• Significantly reduced potency in central nervous system assays (less than 1/345th and 1/5000th) compared to peripheral assays suggests poor blood-brain barrier penetration.

Conclusions:

• L-659,066 is a selective alpha-2 adrenoceptor antagonist with limited efficacy in the central nervous system.
• Its poor penetration of the blood-brain barrier is a key characteristic differentiating it from L-657,743.
• These findings highlight L-659,066's potential utility for studying peripherally mediated alpha-2 adrenoceptor functions.