Name:	AZD3480
Other Names:	ispronicline, TC-1734
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral small molecule
Mechanisms:	AZD3480 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal α4β2 nicotinic (nAChR) receptors.
Development Status:	investigational in U.S.
FDA Phase:	Inactive
Primary Medical Role:	AZD3480 enhances the release of acetylcholine from the cortex. By either acute or repeated administration, AZD3480 exhibits memory-enhancing properties in rats and mice. It is neuroprotective following excitotoxic insult and protects against alterations of synaptic transmission induced by deprivation of glucose and oxygen in rat hippocampal slices (Gatto et al., 2004).
Role in Alzheimer's Disease:	AZD3480 has been tested in normal elderly human subjects with age-associated memory impairment (Dunbar et al., 2007) in a double-blind, placebo-controlled cross-over study, which tested ascending oral doses in the range of 50-150 mg given as a single morning dose for a period of 3 weeks. Cognitive function was assessed with the computerized Cognitive Drug Research (CDR) test battery. A peak in beneficial cognitive effect was observed in attention and episodic memory, at 50 mg dose, although beneficial effects were observed across the dose range. ClinicalTrials.gov NCT00501111 was completed August 2008. In the 12-week placebo-controlled study, known as the Sirocco trial, neither the active comparator donepezil nor AZD3480 met the trial’s criteria for statistical significance on the primary outcome measure, ADAS-Cog (Alzheimer’s Disease Assessment Scale – Cognition Subscale.) Both results were impacted by an improvement in the placebo group.
Pharmacological Role:	AZD3480 has a half-life of 2 hours, which contrasts with the long-lasting improvement in working memory (18 hours- days) in object recognition and radial arm maze tests in rats and mice (Gatto et al., 2004). AZD3480 is highly selective for CNS α4β2 and is reported to have no detectable effects on muscle or ganglionic nAChRs (Dunbar and Kuchibhatla, 2006) in mammalian cells. In healthy male volunteers, Cmax of AZD3480 was reached around 1 to 2 hours postdose, and mean terminal half-life (t1/2) ranged from 3 to 5.3 hours (single doses) and from 2.7 to 8.8 hours (repeated doses). No accumulation of TC- 1734 was observed after 10 days. Renal clearance appeared to be a minor method of elimination of TC-1734 and TC- 1784. A high interindividual variability was noted for all parameters (Dunbar et al., 2006).
Side Effects:	In human subjects (young, healthy male volunteers) AZD3480 was well tolerated. No changes of clinical significance were seen on laboratory and cardiovascular parameters. Adverse events were generally of mild to moderate intensity, with dizziness and headache being reported most frequently (Dunbar et al., 2006). In normal elderly subjects with age- associated memory impairment, AZD3480 was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, hematology, urine analysis, vital signs, standard electrocardiogram (ECG), or Holter monitoring, i.e., portable continuous ECG. The most frequent drug-induced adverse event was light-headedness (dizziness) (Dunbar et al., 2007). Phase 1 clinical trials demonstrated a favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. Behavioral sensitization does not develop following repeated administration of AZD3480 (Gatto et al., 2004). In preclinical studies, AZD3480 has been tested in acute and chronic oral toxicity studies in mice, rats, and dogs and is well tolerated (Gatto et al., 2004).
Companies:	AstraZeneca Pharmaceuticals LP, Targacept, Inc.
Notes:	AstraZeneca announced on July 8, 2009 that AZD3480 development will be focused in attention deficit/hyperactivity disorder (ADHD). AstraZeneca also announced that for Alzheimer Disease, development of AZD1446AZD1446 has been prioritized over further development of AZD3480. This record updated September 14, 2010.

References

Dunbar G, Boeijinga PH, Demazières A, Cisterni C, Kuchibhatla R, Wesnes K, Luthringer R. Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology (Berl). 2007 May;191(4):919-29. Abstract

Dunbar GC, Inglis F, Kuchibhatla R, Sharma T, Tomlinson M, Wamsley J. Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI). J Psychopharmacol. 2007 Mar 1;21(2):171-8. Abstract

Dunbar G, Demazières A, Monreal A, Cisterni C, Metzger D, Kuchibhatla R, Luthringer R. Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers. J Clin Pharmacol. 2006 Jul;46(7):715-26. Abstract

Dunbar GC, Kuchibhatla R. Cognitive enhancement in man with ispronicline, a nicotinic partial agonist. J Mol Neurosci. 2006;30(1-2):169-72. Abstract

Geerts H. Ispronicline (Targacept). Curr Opin Investig Drugs. 2006 Jan;7(1):60-9. Abstract

Lippiello P, Letchworth SR, Gatto GJ, Traina VM, Bencherif M. Ispronicline: a novel alpha4beta2 nicotinic acetylcholine receptor-selective agonist with cognition- enhancing and neuroprotective properties. J Mol Neurosci. 2006;30(1-2):19-20. Abstract

Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier L, Dunbar G, Bencherif M. TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev. 2004 Jan 1;10(2):147-66. Abstract