N-Metilfenetilamin

N-Metilfenetilamin
	Diğer adlar N-Methyl-2-phenylethanamine; N-Methylphenethylamine; N-Methyl-β-phenethylamine
Tanımlayıcılar
CAS numarası	589-08-2;
3D model (JSmol)	Etkileşimli görüntü;
ChemSpider	11019;
ECHA InfoCard	100.008.758
PubChem CID	11503;
CompTox Bilgi Panosu (EPA)	DTXSID10207629 ;
	InChI InChI=1/C9H13N/c1-10-8-7-9-5-3-2-4-6-9/h2-6,10H,7-8H2,1H3;
	SMILES N(CCc1ccccc1)C;
Özellikler
Kimyasal formül	H13N
Molekül kütlesi	27,11 g mol−1
Görünüm	Renksiz sıvı
Yoğunluk	0.93 g/mL
Kaynama noktası	203
	Aksi belirtilmediği sürece madde verileri, Standart sıcaklık ve basınç koşullarında belirtilir (25 °C [77 °F], 100 kPa).

N-Metilfenetilamin (NMPEA) insanlarda bir iz amin olan fenetilaminden (PEA) türetilmiş, doğal olarak oluşan bir iz amin nöromodülatörüdür.^[1] İnsan idrarında (<1 mg 24 saat) tespit edilir^[2] ve pheniletanolamin N-metiltransferaz ile fenetilaminin substrat olarak kullanılmasından üretilir. PEA ve NMPEA alkoloiddir ve bir dizi farklı bitki türünde bulunur.^[3] Bazı Akasya türleri, örn A. rigidula oldukça fazla NMPEA (~2300-5300 ppm) içerir.^[4] NMPEA pek çok gıdada düşük konsantrasyonda (< 10 ppm) bulunur.^[5]

NMPEA amfetamin'in bir pozisyonel izomeridir.^[6]

Kimya

Görünüş olarak, NMPEA renksiz bir sıvıdır. NMPEA bir zayıf bazdır ve pK_a = 10.14; pK_b = 3.86 değerlerine sahiptir.^[7] Erime noktası 162-164 °C olan hidroklorür tuzu oluşturur.^[8]

NMPEA ticari olarak kullanılabilir olsa da, çeşitli yöntemlerle sentezlenebilir. Eski bir sentez metodu Carothers ve arkadaşları tarafından fenetilamin'in p-toluensulfonamid'ine dönüştürülmesini içerir, ardından metil iyodür kullanılarak N-metilasyon, sonra sülfonamid'in hidrolizi gerçekleşir. Daha yeni bir yöntemde, benzer ilke ile NMPEA'nın N-metil grubunun ¹⁴C ile radyo etiketlenmesi kullanılır, fenetilaminin trifloroasetamid'e dönüştürülmesi ile başlar. Önce N-metile edilip (bu özel durumda ¹⁴C etiketli metil iyodür kullanılır) amid hidrolize edilir.^[9]

NMPEA sıçan beyin mitokondrisinde hem MAO-A (K)_M = 58.8 mm) hem MAO-B (K)_M = 2 mm) için substrattır.^[10]

Farmakoloji

NMPEA, epinefrinin 1/350 katı güce sahip bir presördür.^[11]

Ana bileşeni gibi PEA ve izomeri amfetamin gibi, NMPEA güçlü bir insan iz amin ilişkili reseptör 1 (hTAAR1) agonistidir.^[12]^[13] Fenetilamin, amfetamin ve diğer sıçan metilfenetilaminleri ile kıyaslanabilir farmakodinamik ve toksikodinamik özelliklere sahiptir.

PEA gibi, NMPEA da ilk geçiş metabolizmasında monoamin oksidaz tarafından görece hızlı metabolize olur; her iki bileşik de tercihen MAO-B tarafından metabolize olur.

Zehirbilim

NMPEA'nın HCl tuzunun "en az öldürücü dozu (fare, i.p.)" 203 mg/kg'dır;^[14] Aynı tuzun farelerde oral alımında LD₅₀ değeri 685 mg/kg'dır.^[15]

NMPEA'nın akut toksisite çalışmaları sonrası farelere intervenöz uygulamada LD₅₀ = 90 mg/kg olarak bulunmuştur.^[16]

Kaynakça

^ "Studies on lung N-methyltransferases, a pharmacological approach". Naunyn Schmiedebergs Arch. Pharmacol. 313 (3). Eylül 1980. ss. 263-8. doi:10.1007/bf00505743. PMID 7432557.
^ G. P. Reynolds and D. O. Gray (1978) J. Chrom. B: Biomedical Applications 145 137–140.
^ T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochemistry 16 9–18.
^ B. A. Clement, C. M. Goff and T. D. A. Forbes (1998) Phytochemistry 49 1377–1380.
^ G. B. Neurath et al. (1977) Fd. Cosmet. Toxicol. 15 275–282.
^ "Rat brain-uptake index for phenylethylamine and various monomethylated derivatives". Neurochem. Res. 38 (4). Nisan 2013. ss. 842-6. doi:10.1007/s11064-013-0988-1. PMID 23389662.
^ W.H. Carothers, C. F. Bickford and G. J. Hurwitz (1927) J. Am. Chem. Soc. 49 2908–2914.
^ C. Z. Ding et al. (1993) J. Med. Chem. 36 1711–1715.
^ I. Osamu (1983) Eur. J. Nucl. Med. 8 385–388.
^ O. Suzuki, M. Oya and Y. Katsumata (1980) Biochem. Pharmacol. 29 2663–2667.
^ W. H. Hartung (1945) Ind. Eng. Chem. 37 126–137.
^ Broadley KJ (Mart 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3). ss. 363-375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
^ "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5). Mayıs 2005. ss. 274-281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors.
^ A. M. Hjort (1934) J. Pharm. Exp. Ther. 52 101–112.
^ C. M. Suter and A. W. Weston (1941) J. Am. Chem. Soc. 63 602–605.
^ A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther. 106 341–345.

[Pendleton_263–8-1] "Studies on lung N-methyltransferases, a pharmacological approach". Naunyn Schmiedebergs Arch. Pharmacol. 313 (3). Eylül 1980. ss. 263-8. doi:10.1007/bf00505743. PMID 7432557.

[2] G. P. Reynolds and D. O. Gray (1978) J. Chrom. B: Biomedical Applications 145 137–140.

[3] T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochemistry 16 9–18.

[4] B. A. Clement, C. M. Goff and T. D. A. Forbes (1998) Phytochemistry 49 1377–1380.

[5] G. B. Neurath et al. (1977) Fd. Cosmet. Toxicol. 15 275–282.

[NMPH-6] "Rat brain-uptake index for phenylethylamine and various monomethylated derivatives". Neurochem. Res. 38 (4). Nisan 2013. ss. 842-6. doi:10.1007/s11064-013-0988-1. PMID 23389662.

[Car-7] W.H. Carothers, C. F. Bickford and G. J. Hurwitz (1927) J. Am. Chem. Soc. 49 2908–2914.

[8] C. Z. Ding et al. (1993) J. Med. Chem. 36 1711–1715.

[9] I. Osamu (1983) Eur. J. Nucl. Med. 8 385–388.

[10] O. Suzuki, M. Oya and Y. Katsumata (1980) Biochem. Pharmacol. 29 2663–2667.

[11] W. H. Hartung (1945) Ind. Eng. Chem. 37 126–137.

[Trace_Amines-12] Broadley KJ (Mart 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3). ss. 363-375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...

[Renaissance_GPCR-13] "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5). Mayıs 2005. ss. 274-281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors.

[14] A. M. Hjort (1934) J. Pharm. Exp. Ther. 52 101–112.

[15] C. M. Suter and A. W. Weston (1941) J. Am. Chem. Soc. 63 602–605.

[16] A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther. 106 341–345.

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