Antalarmin

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IUPAC_name = N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo [3,2-e] pyrimidin-4-amine

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CAS_number = 157284-96-3
synonyms = Antalarmin
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PubChem = 177990
DrugBank =
C = 24 | H = 34 | N = 4
molecular_weight = 378.55 g/mol
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legal_status = Legal
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Antalarmin is a drug which acts as a CRF-1 antagonist.

Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress and drug addiction. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress. Chronic release of CRF and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, depression, and development of high blood pressure and consequent cardiovascular problems. [Zoumakis E, Rice KC, Gold PW, Chrousos GP. Potential uses of corticotropin-releasing hormone antagonists. "Annals of the New York Academy of Sciences". 2006 Nov;1083:239-51.]

Antalarmin is a non-peptide drug which blocks the CRF-1 receptor, and consequently reduces the release of ACTH in response to chronic stress. [Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP. In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. "Endocrinology". 1996 Dec;137(12):5747-50.] This has been demonstrated in animals to reduce the behavioural responses to stressful situations, [Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF, Licinio J, Wong ML, Chrousos GP, Webster E, Gold PW. The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress. "Endocrinology". 1999 Jan;140(1):79-86.] and it is proposed that antalarmin itself, or more likely newer CRF antagonist drugs still under development, [Nielsen DM, Carey GJ, Gold LH. Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice. "European Journal of Pharmacology". 2004 Sep 19;499(1-2):135-46.] could be useful for reducing the adverse health consequences of chronic stress in humans, as well as having possible uses in the treatment of conditions such as anxiety, depression and drug addiction. [McCarthy JR, Heinrichs SC, Grigoriadis DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. "Current Pharmaceutical Design". 1999 May;5(5):289-315.]

Results so far have had limited success, with various CRF antagonists being tested, which showed some antidepressant effects, but failed to produce an effect comparable with conventional antidepressant drugs. [Jutkiewicz EM, Wood SK, Woods JH. The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats. "Psychopharmacology (Berlin)". 2005 July; 180(2): 215–223.] However more positive results were seen when antalarmin was combined with an SSRI antidepressant, suggesting a potential for synergistic effect. [Ducottet C, Griebel G, Belzung C. Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice. "Progress in Neuropsychopharmacology and Biological Psychiatry". 2003 Jun;27(4):625-31.] Encouraging results have also been observed using antalarmin as a potential treatment for anxiety [Zorrilla EP, Valdez GR, Nozulak J, Koob GF, Markou A. Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat. "Brain Research". 2002 Oct 18;952(2):188-99.] [Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, Gold PW. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. "Proceedings of the National Academy of Sciences USA". 2000 May 23;97(11):6079-84.] and stress-induced hypertension. [Briscoe RJ, Cabrera CL, Baird TJ, Rice KC, Woods JH. Antalarmin blockade of corticotropin releasing hormone-induced hypertension in rats."Brain Research". 2000 Oct 27;881(2):204-7.]

Chronic antalarmin treatment also showed antiinflammatory effects and has been suggested as having potential uses in the treatment of inflammatory conditions such as arthritis, [Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE, Chrousos GP, McCarthy EF, Rice KC, Gold PW, Sternberg EM. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. "Journal of Rheumatology". 2002 Jun;29(6):1252-61.] as well as stress-induced gastrointestinal ulcers [Gabry KE, Chrousos GP, Rice KC, Mostafa RM, Sternberg E, Negrao AB, Webster EL, McCann SM, Gold PW. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. "Molecular Psychiatry". 2002;7(5):474-83, 433.] and irritable bowel syndrome. [Greenwood-Van Meerveld B, Johnson AC, Cochrane S, Schulkin J, Myers DA. Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats. "Neurogastroenterology and Motility". 2005 Jun;17(3):415-22.] [Martinez V, Taché Y. CRF1 receptors as a therapeutic target for irritable bowel syndrome. "Current Pharmaceutical Design". 2006;12(31):4071-88.]

Mixed results have been seen in research into the use of antalarmin and other CRF-1 antagonists in the treatment of drug addiction disorders. Tests of antalarmin on cocaine use in cocaine-addicted monkeys produced only slight reductions of use that were not statistically significant, [Mello NK, Negus SS, Rice KC, Mendelson JH. Effects of the CRF1 antagonist antalarmin on cocaine self-administration and discrimination in rhesus monkeys. "Pharmacology, Biochemistry and Behaviour". 2006 Dec;85(4):744-51.] however in tests on cocaine-addicted rats, antalarmin did prevent dose escalation with prolonged use, suggesting that it might stabilise cocaine use and prevent it increasing over time, although without consistently reducing it. [Specio SE, Wee S, O’Dell LE, Boutrel B, Zorrilla EP and Koob GF. CRF1 receptor antagonists attenuate escalated cocaine self-administration in rats. "Psychopharmacology (Berlin)". 2008 Feb;196(3):473-482.]

Antalarmin also showed positive effects in reducing withdrawal syndrome from chronic opioid use, [Stinus L, Cador M, Zorrilla EP, Koob GF. Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. "Neuropsychopharmacology". 2005 Jan;30(1):90-8.] and significantly reduced self-administration of ethanol in ethanol-addicted rodents. [Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. "Biological Psychiatry". 2007 Jan 1;61(1):78-86.] [Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ. Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout. "Pharmacology, Biochemistry and Behaviour". 2007 Apr;86(4):813-21.] [Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Lê AD. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. "Psychopharmacology (Berlin)". 2007 Dec;195(3):345-55.]

ee also

* CP-154,526
* Pexacerfont
* Corticotropin releasing hormone antagonist

External links

* [http://www.iitri.org/Newsletters/NL-Spring-05-1.shtml Tox Battery Prepares Antalarmin for Clin Trials]

References