الأمينات النزرة (بالإنجليزية: Trace amines) هي مجموعة من ناهضات المستقبل المرتبط بالأمين النزر1 داخلية المنشأ [1] -أي معدِّلات عصبية ذات مفعول أحادي الأمين[2][3][4]- ذات صلة بنيوية وأيضية بالنواقل العصبية أحادية الأمين الكلاسيكية.[5] مقارنة بالأمينات الكلاسيكية فهي تتواجد بتراكيز نزرة (منخفضة جدا)،[5] وهي متوزعة بشكل متغاير في الأنسجة العصبية المحيطية بأدمغة الثدييات وتُظهِر معدلات أيضية عالية.[5][6] رغم أن بالإمكان تخليقها داخل أنظمة رئيسية لناقل عصبي أحادي الأميني.[7] يوجد دليل يقترح أن بعضها قد يملك أنظمة نقل عصبية أحادية الأمين مستقلة خاصة بها.[2]
معلومات سريعة أمين نزر, معرفات الصنيف ...
إغلاق
تلعب الأمينات النزرة أدوارا معتبرة في تنظيم كمية النواقل العصبية أحادية الأمين في الشق المشبكي للعصبونات أحادية الأمين ذات TAAR1 مشترك الموقع.[6] ولديها تأثيرات قبل مشبكية محددة جيدا مشابهة لتأثيرات الأمفيتامين على هذه العصبونات أحادية الأمين عبر تنشيط TAAR1.[3][4] بشكل خاص تنشيط TAAR1 في العصبونات التي نعزز التحرير [ملاحظة 1] لمنع إعادة امتصاص الناقل العصبي أحادي الأمين من الشق الشبكي وكذلك منع الإطلاق العصبوني.[6][8] يملك الفينيثيلامين والأمفيتامين نظائر ديناميكية دوائية في عصبونات الدوبامين البشرية، حيث يقوم كلا المركبين بإحداث تدفق من الناقل أحادي الأميني الحويصلي 2 (VMAT2) [7][9] وتنشيط TAAR1 بفعالية متماثلة تقريبا.[6]
مثل الدوبامين والنورإيبينيفرن والسيروتونين، للأمينات النزرة دور في مجموعة واسعة من الاضطرابات البشرية ذات تأثيرات على الإدراك مثل اضطراب نقص الانتباه مع فرط النشاط (ADHD)،[3][4][10] الاكتئاب[3][4] والفصام،[2][3][4] وأخرى غيرها.[3][4][10]
القصور الوظيفي للأمينات نزرة الفعل متعلق بشكل خاص باضطراب نقص الانتباه مع فرط النشاط لأن تراكيز الفينيثيلامين في بلازما الدم والبول منخفضة بشكل معتبر لدى الأفراد المرضى بالـADHD مقارنة بالتراكيز المعيارية وأكثر الأدوية التي توصف للـADHD -وهي الأمفيتامين والميثيل فينيدات- تزيد من التخليق الحيوي للفينيثيلامين لدى الأفراد المستجيبين للعلاج المصابين بالـADHD.[3][11] أشارت مراجعة منهجية للمؤشرات الحيوية الخاصة بالـADHD أن مستويات الفينيثيلامين في البول يمكن أن تكون مؤشر حيوي تشخيصي للـADHD.[11]
بعض الأمينات النزرة مثل الفينيثيلامين تثبط وظيفيا الناقل أحادي الأمين الحويصلي ناقل أحادي الأمين الحويصلي 2 بينما لا تفعل أمينات نزرة أخرى ذلك. الأمينات النزرة التي تثبط VMAT2 تعمل في عصبونات أحادية الأمين لا تفرز نواقل عصبية بالكفاءة التي تفرز بها العصبونات الأخرى.
Berry MD (يناير 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials. ج. 2 ع. 1: 3–19. DOI:10.2174/157488707779318107. PMID:18473983. changes in trace amines, in particular PE, have been identified as a possible factor for the onset of attention deficit/hyperactivity disorder (ADHD) [5, 27, 43, 78]. PE has been shown to induce hyperactivity and aggression, two of the cardinal clinical features of ADHD, in experimental animals [100]. Hyperactivity is also a symptom of phenylketonuria, which as discussed above is associated with a markedly elevated PE turnover [44]. Further, amphetamines, which have clinical utility in ADHD, are good ligands at trace amine receptors [2]. Of possible relevance in this aspect is modafanil, which has shown beneficial effects in ADHD patients [101] and has been reported to enhance the activity of PE at TAAR1 [102]. Conversely, methylphenidate, which is also clinically useful in ADHD, showed poor efficacy at the TAAR1 receptor [2]. In this respect it is worth noting that the enhancement of functioning at TAAR1 seen with modafanil was not a result of a direct interaction with TAAR1 [102].
More direct evidence has been obtained recently for a role of trace amines in ADHD. Urinary PE levels have been reported to be decreased in ADHD patients in comparison to both controls and patients with autism [103-105]. Evidence for a decrease in PE levels in the brain of ADHD patients has also recently been reported [4]. In addition, decreases in the urine and plasma levels of the PE metabolite phenylacetic acid and the precursors phenylalanine and tyrosine have been reported along with decreases in plasma tyramine [103]. Following treatment with methylphenidate, patients who responded positively showed a normalization of urinary PE, whilst non-responders showed no change from baseline values [105].
Lindemann L، Hoener MC (مايو 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. ج. 26 ع. 5: 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...Both dopamine and 3-methoxytyramine, which do not undergo further N-methylation, are partial agonists of TAAR1 (TA1). ...
The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders [7,8,36]. Clinical studies report increased β-PEA plasma levels in patients suffering from acute schizophrenia [37] and elevated urinary excretion of β-PEA in paranoid schizophrenics [38], which supports a role of TAs in schizophrenia. As a result of these studies, β-PEA has been referred to as the body's 'endogenous amphetamine' [39]
Broadley KJ (مارس 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. ج. 125 ع. 3: 363–375. DOI:10.1016/j.pharmthera.2009.11.005. PMID:19948186. 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 ... 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 ...
Sotnikova TD، Caron MG، Gainetdinov RR (أغسطس 2009). "Trace amine-associated receptors as emerging therapeutic targets". Mol. Pharmacol. ج. 76 ع. 2: 229–35. DOI:10.1124/mol.109.055970. PMC:2713119. PMID:19389919. Although the functional role of trace amines in mammals remains largely enigmatic, it has been noted that trace amine levels can be altered in various human disorders, including schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, and phenylketonuria (Boulton, 1980; Sandler et al., 1980). It was generally held that trace amines affect the monoamine system indirectly via interaction with plasma membrane transporters [such as plasma membrane dopamine transporter (DAT)] and vesicular storage (Premont et al., 2001; Branchek and Blackburn, 2003; Berry, 2004; Sotnikova et al., 2004). ...
Furthermore, DAT-deficient mice provide a model to investigate the inhibitory actions of amphetamines on hyperactivity, the feature of amphetamines believed to be important for their therapeutic action in ADHD (Gainetdinov et al., 1999; Gainetdinov and Caron, 2003). It should be noted also that the best-established agonist of TAAR1, β-PEA, shared the ability of amphetamine to induce inhibition of dopamine-dependent hyperactivity of DAT-KO mice (Gainetdinov et al., 1999; Sotnikova et al., 2004).
Furthermore, if TAAR1 could be proven as a mediator of some of amphetamine's actions in vivo, the development of novel TAAR1-selective agonists and antagonists could provide a new approach for the treatment of amphetamine-related conditions such as addiction and/or disorders in which amphetamine is used therapeutically. In particular, because amphetamine has remained the most effective pharmacological treatment in ADHD for many years, a potential role of TAAR1 in the mechanism of the "paradoxical" effectiveness of amphetamine in this disorder should be explored.
Scassellati C، Bonvicini C، Faraone SV، Gennarelli M (أكتوبر 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry. ج. 51 ع. 10: 1003–1019.e20. DOI:10.1016/j.jaac.2012.08.015. PMID:23021477. Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110
