AZD-2327

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| image = AZD-2327.svg

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| routes_of_administration = Oral

| class = δ-Opioid receptor agonist

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| CAS_number = 875647-81-7

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1197281-62-1 (hemifumarate)

| PubChem = 11525765

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| ChemSpiderID = 9700551

| UNII = 3Q7J827527

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| synonyms = AZD 2327; AZD2327

| IUPAC_name = 4-[(R)-(3-aminophenyl)-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]methyl]-N,N-diethylbenzamide

| C=29 | H=35 | F=1 | N=4 | O=1

| SMILES = CCN(CC)C(=O)C1=CC=C(C=C1)[C@H](C2=CC(=CC=C2)N)N3CCN(CC3)CC4=CC=C(C=C4)F

| StdInChI = 1S/C29H35FN4O/c1-3-33(4-2)29(35)24-12-10-23(11-13-24)28(25-6-5-7-27(31)20-25)34-18-16-32(17-19-34)21-22-8-14-26(30)15-9-22/h5-15,20,28H,3-4,16-19,21,31H2,1-2H3/t28-/m1/s1

| StdInChIKey = XGFLMBBZEPJGHY-MUUNZHRXSA-N

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AZD-2327 is a δ-opioid receptor agonist which was under development for the treatment of depressive disorders and anxiety disorders but was never marketed.{{cite web | title=AZD 2327 | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800024943 | access-date=21 October 2024}}{{cite web | title=Delving into the Latest Updates on AZD-2327 with Synapse | website=Synapse | date=19 October 2024 | url=https://synapse.patsnap.com/drug/bd0f9b65bcbc41b3ad7962bc57bd44ab | access-date=21 October 2024}}{{cite journal | vauthors = Mandrioli R, Mercolini L | title = Discontinued anxiolytic drugs (2009 - 2014) | journal = Expert Opinion on Investigational Drugs | volume = 24 | issue = 4 | pages = 557–573 | date = April 2015 | pmid = 25557457 | doi = 10.1517/13543784.2014.998335 }}{{cite journal | vauthors = Dripps IJ, Jutkiewicz EM | title = Delta Opioid Receptors and Modulation of Mood and Emotion | journal = Handbook of Experimental Pharmacology | volume = 247 | issue = | pages = 179–197 | date = 2018 | pmid = 28993835 | doi = 10.1007/164_2017_42 | isbn = 978-3-319-95131-7 | series = Handbook of Experimental Pharmacology }}{{cite journal | vauthors = Richards EM, Mathews DC, Luckenbaugh DA, Ionescu DF, Machado-Vieira R, Niciu MJ, Duncan WC, Nolan NM, Franco-Chaves JA, Hudzik T, Maciag C, Li S, Cross A, Smith MA, Zarate CA | title = A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression | journal = Psychopharmacology | volume = 233 | issue = 6 | pages = 1119–1130 | date = March 2016 | pmid = 26728893 | pmc = 5103283 | doi = 10.1007/s00213-015-4195-4 }} It is taken by mouth.

Pharmacology

The drug showed antidepressant- and anxiolytic-like effects as well as locomotor-stimulating effects in animal models. It had reduced induction of seizures and locomotor hyperactivity compared to other δ-opioid receptor agonists. The doses required for stimulant-like activity were 3- to 10-fold greater than the doses that produced antidepressant- and anxiolytic-like effects. The drug appears to have a very low misuse potential based on animal studies.{{cite journal | vauthors = Hudzik TJ, Pietras MR, Caccese R, Bui KH, Yocca F, Paronis CA, Swedberg MD | title = Effects of the δ opioid agonist AZD2327 upon operant behaviors and assessment of its potential for abuse | journal = Pharmacology, Biochemistry, and Behavior | volume = 124 | pages = 48–57 | date = September 2014 | pmid = 24857840 | doi = 10.1016/j.pbb.2014.05.009 }} In addition to its δ-opioid receptor agonist activity, AZD-2327 has been reported to act as a cytochrome P450 CYP3A4 inhibitor.{{cite journal | vauthors = Guo J, Zhou D, Li Y, Khanh BH | title = Physiologically based pharmacokinetic modeling to predict complex drug-drug interactions: a case study of AZD2327 and its metabolite, competitive and time-dependent CYP3A inhibitors | journal = Biopharmaceutics & Drug Disposition | volume = 36 | issue = 8 | pages = 507–519 | date = November 2015 | pmid = 26081137 | doi = 10.1002/bdd.1962 }}

It has been found to inhibit the release of norepinephrine caused by anxiety and was able to do so as much as the benzodiazepine diazepam.{{cite journal | vauthors = Hudzik TJ, Maciag C, Smith MA, Caccese R, Pietras MR, Bui KH, Coupal M, Adam L, Payza K, Griffin A, Smagin G, Song D, Swedberg MD, Brown W | title = Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 338 | issue = 1 | pages = 195–204 | date = July 2011 | pmid = 21444630 | doi = 10.1124/jpet.111.179432 }} However, AZD-2327 could be advantageous to benzodiazepines because these drugs often cause rapid tolerance and dependence.{{cite journal | vauthors = Rosenberg HC, Chiu TH | title = Time course for development of benzodiazepine tolerance and physical dependence | journal = Neuroscience and Biobehavioral Reviews | volume = 9 | issue = 1 | pages = 123–131 | date = March 1985 | pmid = 2858077 | doi = 10.1016/0149-7634(85)90038-7 }} In contrast to benzodiazepines, AZD-2327 may have less or no potential for tolerance in terms of its anxiolytic-like effects.

History

AZD-2327 was first described by 2004 and was first described in the scientific literature in 2009. The development of AZD-2327 was discontinued in 2010. It reached phase 2 clinical trials for both depressive disorders and anxiety disorders prior to its discontinuation. No reason was given for the discontinuation of its development. However, the drug was found to be ineffective for major depressive disorder in a phase 2 clinical trial.{{cite journal | vauthors = Sakurai H, Yonezawa K, Tani H, Mimura M, Bauer M, Uchida H | title = Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry | journal = Pharmacopsychiatry | volume = 55 | issue = 4 | pages = 193–202 | date = July 2022 | pmid = 35045580 | pmc = 9259184 | doi = 10.1055/a-1714-9097 }}{{cite journal | vauthors = Sanches M, Quevedo J, Soares JC | title = New agents and perspectives in the pharmacological treatment of major depressive disorder | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 106 | issue = | pages = 110157 | date = March 2021 | pmid = 33159975 | pmc = 7750246 | doi = 10.1016/j.pnpbp.2020.110157 }} AZD-2327 was developed by AstraZeneca.