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Definition
Antazoline, an imidazoline derivative with antihistaminic properties, has been shown to exert neuroprotection against hypoxia and N-methyl-D-aspartate (NMDA) toxicity in cerebellar and striatal neuronal cultures through a voltage-dependent blockade of glutamatergic NMDA receptors.

Discovery
Berdeu D et al., in 1997 analysed antazoline increases insulin secretion and improves glucose tolerance in rats and dogs 1. Milhaud D et al., in 2003 studied the neuroprotective activity of antazoline against neuronal damage induced by limbic status epilepticus. Their results suggest antazoline is neuroprotective in vivo in the intra-pyriform pilocarpine-induced status epilepticus model 2.

Structural Characteristics
Antazoline structure is 2-(N-Phenyl-N-benzyl-aminomethyl)-imidazoline. Several antazoline derivatives have been identified. Structure of antazoline maleate is N-(2-Amino-ethyl)-2-(benzyl-phenyl-amino)-acetamide · maleate, antazoline HCl structure is Benzyl-(4,5-dihydro-1H-imidazol-2-ylmethyl)-phenyl-amine · HCl and that of antazoline H3PO4 is 2-(N-Phenyl-N-benzyl-aminomethyl)-imidazoline · H3PO4, antazoline H2SO4 structure is 2-(N-Phenyl-N-benzyl-aminomethyl)-imidazoline · 0.5 H2SO4 3

A simple, precise, and accurate spectrophotometric determination of antazoline salts was developed by improving the ceric sulfate procedure. An appreciable increase in color stability was attained by the controlled addition of perchloric acid to the ceric reagent prior to interaction with antazoline at room temperature. Evidence is provided to account for the oxidation of antazoline at the expense of a complex ceric species 4.

Mode of Action
Didier M et al., showed that imidazolines exert neuroprotection against hypoxia and NMDA toxicity in cerebellar and striatal neuronal cultures, through a voltage-dependent blockade of glutamatergic NMDA receptors. Didier M et al., in 2002  report that in striatal neuronal cultures from mouse embryos the imidazoline compound, antazoline, inhibits voltage-gated Ca2+ channels by acting at a phencyclidine-like site. This effect was fast, fully reversible, voltage-dependent and predominant on P/Q- and N-type Ca2+ channels. Taken together, these results suggest that imidazolines may elicit neuroprotective effects also by decreasing the release of glutamate through inhibition of presynaptic Ca2+ channels 2,5.

Antazoline inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many adenosine 5'-triphosphate (ATP)-sensitive K+ channels are open in the beta-cell membrane. They also reduced the acceleration of 86Rb efflux caused by diazoxide, an opener of ATP-sensitive K+ channels.  ATP-sensitive and voltage-sensitive K+ currents were measured in single beta-cells by the whole-cell mode of the patch-clamp technique. Antazoline more markedly inhibited the ATP-sensitive than the voltage-sensitive current, an effect previously observed with phentolamine. Antazoline reversed the inhibition of insulin release caused by diazoxide (through opening of ATP-sensitive K+ channels) or by clonidine (through activation of alpha 2-adrenoceptors) in a concentration-dependent manner 6.

Functions

Neuroprotective effects, antazoline drugs exert neuroprotective effects in cerebral ischaemia models. They also have effects against mouse cerebellar and striatal neuronal death induced by (NMDA) through the blockade of NMDA currents 2.

Antazoline antagonists of α-2-adrenoceptors increase insulin release in vitro by blockade of ATP-sensitive K+ channels in β-cells rather than to their interaction with the adrenoceptor 6.

Stimulate insulin secretion, in dogs provided with a venous pancreatico-duodenal bypass, antazoline (0.5 mg/kg i.v.) induced an immediate and transient increase in insulin and somatostatin but not in glucagon pancreatico-duodenal outputs. Intravenously and orally administered, the imidazoline antazoline is able to stimulate insulin secretion in vivo and improve glucose tolerance 1.

References

1.     Berdeu D, Puech R, Ribes G, Loubatières-Mariani MM, Bertrand G (1997). Antazoline increases insulin secretion and improves glucose tolerance in rats and dogs. European journal of pharmacology, 324(2-3):233-239.

2.     Milhaud D, Rondouin G, Lerner-Natoli M, Bockaert J, Lafon-Cazal M (2003). Neuroprotective activity of antazoline against neuronal damage induced by limbic status epilepticus. Neuroscience, 120(2):475-484.

3.     Milhaud D, Fagni L, Bockaert J, Lafon-Cazal M (2002). Inhibition of voltage-gated Ca2+ channels by antazoline. Neuroreport., 13:1711-1714.

4.     Marciniec B, Kozak M, Naskrent M, Dettlaff K, Ogrodowczyk M, Stawny  M, Wachowski L (2007). Thermal study of four irradiated imidazoline derivatives in solid state. Journal of Thermal Analysis and Calorimetr., 88(2):337-342.

5.     Omar NM (2006). Improved spectrophotometric determination of antazoline. Journal of Pharmaceutical Sciences, 67(11):1610-1613.

6.     Jonas JC, Plant TD, Henquin JC (1992).  Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta-cells. British journal of Pharmacology. 107(1):8-14.

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