AGN 192403 hydrochloride

AGN 192403 hydrochloride is a selective ligand of imidazoline1 receptor [1].

Imidazoline receptor is the primary receptor for clonidine and other imidazolines. Imidazoline1 receptor (I1 receptor) lowers blood pressure via inhibition of the sympatho actions by imidazolines.

AGN 192403 hydrochloride is a selective ligand of I1 receptor. AGN192403 exhibited affinity for I1 receptor with Ki value of 42 nM and was only 5-fold less potent than clonidine. However, AGN192403 had no agonist and antagonist activities. In monkey and rat, AGN192403 (5000 μg/kg) had no effect on blood pressure [1]. In astrocytes, AGN 192403 inhibited cytochrome c release, lysosomal acridine orange relocation, caspase-9 activation and decrease in mitochondrial potential, cytotoxicities that was induced by naphthazarin. Also, AGN 192403 inhibited mitochondrial dysfunction and cytotoxicities induced by antimycin A and rotenone, inhibitors of mitochondrial respiration [2]. In isolated normotensive rat hearts, AGN192403 inhibited atrial natriuretic peptide (ANP) release induced by moxonidine (10−6 M) [3].

References:
[1] unk SA1, Lai RK, Burke JE,Munk SA1, Lai RK, Burke JE,Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.Munk et al (1996) Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent. J.Med.Chem. 39 1193. PMID: 8632424.Stephen A. Munk,* Ronald K. Lai, James E. Burke, [1].  Munk SA, Lai RK, Burke JE, et al. Synthesis and Pharmacologic Evaluation of 2-endo-Amino-3-exoisopropylbicyclo[2.2.1]heptane: A Potent Imidazoline1 Receptor Specific Agent. J Med Chem, 1996, 39(6): 1193-1195.
[2].  Choi DH, Kim DH, Park YG, et al. Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and mitochondrial inhibitor-induced cytotoxicity in astrocytes. Free Radic Biol Med, 2002, 33(10): 1321-1333.
[3].  Mukaddam-Daher S, Menaouar A, Gutkowska J. Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts. Eur J Pharmacol, 2006, 541(1-2): 73-79.

Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts.[Pubmed:16774751]

Eur J Pharmacol. 2006 Jul 10;541(1-2):73-9.

Imidazoline I1-receptors are present in the heart and may be involved in atrial natriuretic peptide (ANP) release. The following studies investigated whether moxonidine (an antihypertensive imidazoline I1-receptor and alpha2-adrenoceptor agonist) acts directly on the heart to stimulate ANP release, and to characterize the receptor type involved in this action. Perfusion of rat (200-225 g) isolated hearts with moxonidine (10(-6) and 10(-5) M), for 30 min, resulted in ANP release (83+/-29 and 277+/-70 ng/30 min, above basal, respectively), significantly (P<0.01) different from perfusion with buffer (-6+/-31 ng/30 min). ANP release stimulated by moxonidine (10(-6) M) was inhibited by co-perfusion with the antagonists, AGN192403 (imidazoline I1-receptor), phenoxybenzamine (alpha2>alpha1-adrenoceptors), and prazosin (alpha1>alpha2-adrenoceptors), but increased by rauwolscine (alpha2-adrenoceptors). Perfusion with 10(-5) M brimonidine (full alpha2-adrenoceptor agonist) inhibited moxonidine-stimulated ANP release. Similarly, moxonidine (10(-6) M) tended to reduce coronary flow, but significantly increased coronary flow in the presence of brimonidine, which was vasoconstrictive when perfused alone. Coronary flow was reduced by 10(-5) M each, brimonidine>clonidine>moxonidine; while similar bradycardia was observed with clonidine and moxonidine, but not with brimonidine. In conclusion, these results argue in favor of moxonidine acting primarily on imidazoline I1-receptors to release ANP, with both alpha2-adrenoceptor and imidazoline I1-receptors exerting inhibitory inter-relation. In contrast, the coronary vasodilatory effect of moxonidine requires full activation of alpha2-adrenoceptor. The sympatholytic and ANP-releasing effects of moxonidine appear to be mediated by cardiac imidazoline receptors that may be differentially localized. Most importantly, moxonidine can stimulate ANP release from the heart without contribution of the central nervous system.

Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction.[Pubmed:11834614]

Br J Pharmacol. 2002 Feb;135(3):663-72.

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg(-1), respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while alpha(2)-adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I(1)-binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR.