Disease relevance of A-85380

• In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically [1].
• Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs [2].
• The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence [3].

High impact information on A-85380

• Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain [1].
• Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier [1].
• Although A-85380 is reported to be selective for alpha4beta2* nAChRs, we observed that A-85380 completely inhibited [125I]alpha-conotoxin MII binding in rat striatum and that A-85380 blocked >90% of [125I] alpha-conotoxin MII sites in monkey caudate and putamen [4].
• Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380 [5].
• In BALB/c mice, a strain expressing a normal gating phenotype, nicotine (MED: 10 mg/kg, SC), epibatidine (MED: 0.03 mg/kg, IP) and A-85380 (MED: 0.3 mg/kg, IP) predominantly augmented PPI and mecamylamine attenuated these effects [6].

Chemical compound and disease context of A-85380

• Both ABT-594 ((R)-2-chloro-5-(2-azetidinylmethoxy)pyridine) and A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine), novel nicotinic agonists that possess potent non-opioid analgesic properties, have high affinity for neuronal nicotinic acetylcholine receptors (nAChR) but do not elicit the pronounced toxicity of epibatidine [7].

Biological context of A-85380

• (+/-)-Epibatidine (EPIB) and A-85380 are nicotinic acetylcholine receptor (nAChR) agonists that bind to the agonist ([3H]cytisine) binding site with 40 to 50 pM affinity but have different affinities in nAChR subtype selective functional receptor assays [8].
• Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio [9].

Anatomical context of A-85380

• Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM) [10].
• Both i.c.v. infusion and repeated bolus injections into the cerebral aqueduct of an antisense oligonucleotide against the alpha4 subunit significantly attenuated the antinociceptive effects of the nAChR agonist A-85380 in the paw withdrawal test of acute thermal pain [11].
• Finally, as measured by in vivo microdialysis, levels of 5-HT, but not NE, in the i.t. space of the lumber region of the spinal cord were significantly increased following the systemic administration of A-85380 [12].

Associations of A-85380 with other chemical compounds

• In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM) [10].
• The sensitivities of the alpha4beta2 nicotinic acetylcholine receptors to the agonists acetylcholine, 5-I A-85380, and TC-2559 were investigated using the voltage-clamp technique on Xenopus oocytes and using a fluorescent imaging plate reader to measure calcium responses from HEK-293 cells [13].
• In order to develop PET/SPECT nAChRs ligands for detection of subtypes of nAChRs nicotine analogues, epibatidine and A-85380 compounds have been characterized in vitro and investigated in vivo [14].

Gene context of A-85380

• The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM) [10].

Analytical, diagnostic and therapeutic context of A-85380

• To identify the receptor subtypes, we performed [125I]epibatidine autoradiography in the presence of cytisine or A-85380 [15].
• Synthesis of an I-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon [16].
• Mechanism of action of A-85380 in an animal model of depression [17].

References