AR-R 17779 hydrochloride

AR-R 17779 is a selective agonist of α7 nicotinic acetylcholine receptor (α7-nAChR) [1] with an EC50 of 21 μM to rat α7-nAChRs expressed in Xenopus oocytes [2].

Nicotine enhances cognitive functions, e.g. learning, attention, retention and memory in both humans and animals, via activation of brain nicotinic acetylcholine receptors (nAChRs). These receptors are homo- or heteropentameric ligand-gated ion channels. The most common nicotinic receptors found in the brain are the α4β2-nAChR and the α7-nAChR [3].

The expression of CD38, CD138, and Bcl-6, was sensitive to regulation via nAChRs. Daudi cells exposed to AR-R 17779 ± methyllycaconitine (MLA) resulted in only moderate changes in the gene expression of CD38, CD138 and Bcl-6, but AR-R 17779 alone significantly (P< 0.05) increased protein levels of CD38 and CD138. That means the effect of AR-R 17779 was abolished by MLA [4].

Cholesterol is necessary for the homeostasis of acetylcholine receptor (AChR) levels for ion translocation and at the plasmalemma [5]. In ApoE-deficient mice, AR-R 17779 significantly reduced atherosclerotic plaque area in the thoracic aorta, and lowered heart rate, blood pressure, serum triglyceride level and serum total cholesterol level compared with which in Ang II + HFD mice. Treatment with AR-R 17779 in mice did not result in any sickness behavior or apparent abnormalities. At the end of the experiment, the serum concentration of AR-R 17779 was 1.18 ± 0.17 μM. In ApoE-deficient mice, treatment with AR-R 17779 resulted in significantly reduced aortic diameter comparable to control mice (0.81 ± 0.11 mm, p< 0.0001 vs. Ang II + HFD) [1].

References:
[1].  Toru Hashimoto, Toshihiro Ichiki, AyaWatanabe, et al. Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice. Vascular Pharmacology, 2014, 61:49-55.
[2].  Rudy Schreiber, Marion Dalmus and Jean De Vry. Effects of α4/β2- and α7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice. Psychopharmacology, 2002, 159:248-257.
[3].  Marja van Kampen, Karin Selbach, Renate Schneider, et al. AR-R 17779 improves social recognition in rats by activation of nicotinic α7 receptors. Psychopharmacology, 2004, 172:375-383.
[4].  Juan Arredondo, Denys Omelchenko, Alexander I Chernyavsky, et al. Functional role of the nicotinic arm of the acetylcholine regulatory axis in human B-cell lines. Journal of Experimental Pharmacology, 2009, 1:1-7.
[5].  Virginia Borroni and Francisco J. Barrantes. Cholesterol Modulates the Rate and Mechanism of Acetylcholine Receptor Internalization. J. Biol. Chem., 2011, 286(19):17122-32.

Activation of presynaptic alpha7 nicotinic receptors evokes an excitatory response in hippocampal CA3 neurones in anaesthetized rats: an in vivo iontophoretic study.[Pubmed:20105181]

Br J Pharmacol. 2010 Feb 1;159(3):554-65.

BACKGROUND AND PURPOSE: alpha7 Nicotinic receptors have been suggested to play an important role in hippocampal learning and memory. However, the direct action of this receptor subtype on hippocampal pyramidal neurones in vivo has not yet been fully investigated. The availability of selective agonists for alpha7 receptors [AR-R17779 and (R)-(-)-5'-phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP)] has now allowed this role to be investigated. EXPERIMENTAL APPROACH: Single-cell extracellular recordings were made from hippocampal CA3 pyramidal neurones in anaesthetized rats. The effects of nicotine, AR-R17779 and PSAB-OFP, applied either systemically or iontophoretically, were studied on the activity of these neurones. KEY RESULTS: Intravenous injection of cumulative doses of nicotine and PSAB-OFP induced dose-related, significant increases in neuronal firing in the majority of neurones tested. This excitation could be inhibited by intravenous administration of methyllycaconitine (MLA), a selective alpha7 nicotinic receptor antagonist. Furthermore, iontophoretic application of nicotine, AR-R17779 and PSAB-OFP each evoked current-dependent excitation of most CA3 pyramidal neurones studied, and this excitation was antagonized by co-iontophoretic application of MLA. In addition, the excitation induced by iontophoretic application of nicotine, AR-R17779 or PSAB-OFP was also blocked by co-iontophoretic application of either 6,7-dinitroquinoxaline-2,3-dione (DNQX) or D(2)-2-amino-5-phosphonopentanoate (D-AP5), selective N-methyl-D-aspartic acid (NMDA) and non-NMDA receptor antagonists respectively. CONCLUSIONS AND IMPLICATIONS: CA3 pyramidal neurones are modulated by activation of presynaptic alpha7 nicotinic receptors, which, at least in part, enhances glutamate release onto post-synaptic (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and NMDA receptors on these CA3 neurones. This mechanism probably contributes to the effects of nicotine on hippocampal learning and memory.

Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine.[Pubmed:10945867]

J Pharmacol Exp Ther. 2000 Sep;294(3):1112-9.

Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.

(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.[Pubmed:11063601]

J Med Chem. 2000 Nov 2;43(22):4045-50.

Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.