مضادات مستقبلات شبيهات القنب Cannabinoid receptor antagonist

أدى اكتشاف نظام القنب الداخلى إلى تطوير مستقبلات مضادات.مستقبلات أول مضادات مستقبلات شبيهات القنب، ريمونابانت وصفت ، في عام 1994 (على الرغم من أنها هي من الناحية التقنية ناهض منعكس ، وليس مضاد).ريمونابانت يغلق إختياريا مستقبلات سي بي1₁ ولقد ثبت أنه يخفض كمية الغذاء المستهلكة وينظيم عمليةزيادة الوزن بالجسم ، . إذا إنتشار السمنة في جميع أنحاء العالم في تزايد كبير وذلك يؤثر كثيراعلى الصحة العامة. لذا فإن انعدام الكفاءة وكذلك الأدوية ذات الإحتمال الجيد لعلاج السمنة قد أدى إلى زيادة الاهتمام في البحث والتطوير لمضادات مستقبلات شبيهات القنب.

التاريخ

لقرون الحشيش والماريجوانا من القنب الهندي كانابيس ستيفا L. قد استخدمت لأغراض طبية وترفيهية. في عام 1964 فإن المكون الرئيسي النشطC. ساتيفا L., أ⁹-تتراهيدروكانابينول (THC), تم فصله وتوليفه من قبل معامل ماكويلامز . | وهناك نوعان من مستقبلات القنب ، سى بى₁ وسى بى₂, المسؤولة عن الآثار التي تم اكتشافها من التتراهيدروكانابينول ومستنسخ في وقت مبكر من 1990. وفى الوقت الذى قد اكتشفت فيه مستقبلات القنب, أصبح من الأهمية بمكان تحديد ما إذا كانت مشابهات تحدث طبيعيا في الجسم. هذا البحث أدى إلى اكتشاف الذاتية الأولى من الحشيش (endocannabinoid), anandamide (arachidonoyl ethanolamide). endocannabinoids أخرى في وقت لاحق تم العثور على, عملى سبيل المثال 2-AG (2-arachidonoyl glycerol). هذه النتائج أثارت المزيد من الأسئلة حول دور الدوائية والفسيولوجية للنظام من الحشيش. أحيت هذه البحوث اللغط على مضادات مستقبلات الحشيش التي كان من المتسقط حتى تساعد على إجابة هذه الأسئلة. استخدام محفزات الحشيش ، التتراهيدروكانابينول ، في الكثير من الأعمال التحضيرية من أجل تعزيز الشهية هوحقيقة معروفة. هذا الواقع أدى إلى امتداد منطقي وهوحتى حظر أوغلق هذه المستقبلات للقنب قد تكون مفيدة في تقليل الشهية للطعام والاستهلاك الغذائي. ثم اكتشف حتى انسداد مستقبلات سي بي1 مستقبلات تمثل هدفا جديدا الدوائية₁ . أول مستقبل محددCB₁ مضادات مستقبلات كان ريمونابانت, وقد أكتشف في عام 1994.

شبيهات القنب الداخلية تشير الى النظام

نظام شبيهات القنب الداخلية تتضمن مستقبلات القنب ، وبروابط داخلية (endocannabinoids) والانزيمات للتخليق والتدهور.

هناك نوعان من المستقبلات الرئيسية المرتبطة endocannabinoid تشير الى النظام ؛ مستقبلات القنب 1 (سى بى₁) و2 (). جميع المستقبلات هي7-transmembrane G-protein coupled receptors (GPCR) التي تحول دون تراكم الأدينوساين مونوفوسفات الدوري داخل الخلايا. CB₁مستقبلات موجودة في أعلى هجريز في الدماغ ولكن يمكن العثور عليها أيضا في المحيط الخارجي. سى بى2المستقبلات التي يقع معظمها في مأمن والأنظمة المنتجة للدم .

Endocannabinoids are eicosanoids acting as agonists for cannabinoid receptors and they occur naturally in the body. Cannabinoid receptor-related processes are for example involved in cognition, memory, anxiety, control of appetite, القيىء, التصرف الحركى, sensory, اللاإرادي and neuroendocrine responses, immune responses and inflammatory effects. There are two well-characterized endocannabinoids located in the brain and periphery. The first identified was anandamide (arachidonoyl ethanolamide) and the second was 2-AG (2-arachidonoyl glycerol). Additional endocannabinoids include virodhamine (O-arachidonoyl ethanolamine), noladin ether (2-arachidonoyl glyceryl ether) and NADA (N-arachidonoyl dopamine).

Mechanism of action

CB₁ receptors are coupled through G_i/o proteins and inhibit adenylyl cyclase and activate mitogen-activated protein (MAP) kinase. In addition, CB₁ receptors inhibit presynaptic N- and P/Q-type calcium channels and activate inwardly rectifying potassium channels. CB₁ antagonists produce inverse cannabimimetic effects that are opposite in direction from those produced by agonists for these receptors.

CB₁ receptors are highly expressed in hypothalamic areas which are involved in central food intake control and feeding behavior. This strongly indicates that the cannabinoid system is directly involved in feeding regulation. These regions are also interconnected with the mesolimbic dopamine pathway, the so-called "reward" system. Therefore, CB₁ antagonists might indirectly inhibit the dopamine-mediated rewarding properties of food. Peripheral CB₁ receptors are located in the gastrointestinal (GI) tract, liver and in adipose tissue. In the GI, CB₁ receptors are located on nerve terminals in the intestines. Endocannabinoids act at the CB₁ receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal peristalsis and gastric emptying. Thus, antagonism at these receptors can inverse these effects. Also, in peripheral tissues, antagonism of CB₁ receptors increases insulin sensitivity and oxidation of fatty acids in muscles and the liver. A hypothetical scheme for the metabolic effects of CB₁ receptor antagonists is shown in Figure 1.

Drug design

The first approach to develop cannabinoid antagonists in the late 1980s was to modify the structure of THC but the results were disappointing. In the early 1990s new family of cannabinoid agonists was discovered from the NSAID (non-steroidal anti-inflammatory) drug pravadoline which led to the discovery of aminoalkyl indole antagonists with some but limited success. As the search based on the structure of agonists was disappointing it was no surprise that the first potent and selective cannabinoid antagonist belonged to an entirely new chemical family. In 1994 the first selective cannabinoid antagonist, SR141716 (rimonabant), was introduced by Sanofi belonging to a family of 1,5-diarylpyrazoles. ===Rimonabant===

Rimonabant, also known by the systematic name [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamidehydrochloride)], is a 1,5-diarylpyrazole CB₁ receptor antagonist (Figure 2). Rimonabant is not only a potent and highly selective ligand of the CB₁ receptor, but it is also orally active and antagonizes most of the effects of cannabinoid agonists, such as THC, both in vitro and in vivo. Rimonabant has shown clear clinical efficacy for the treatment of obesity.

Binding

Diarylpyrazole derivatives

SR141716 (rimonabant) analogs have recently been described by several groups, leading to a good understanding of the structure-activity relationship (SAR) within this chemical group. While most compounds described are less potent than SR141716, two of them are worth mentioning, SR147778 and AM251.

SR147778 (surinabant), a second generation antagonist, has a longer duration of action than rimonabant and enhanced oral activity. This enhanced duration of action is probably due to the presence of the more metabolically stable ethyl group at the 4-position of its pyrazole ring. Another change is the replacement of the 5-phenyl chlorine substituent by bromine.

The diarylpyrazole derivative, AM251, has been described where chlorine substituent has been replaced by iodine in the para position of the 5-phenyl ring. This derivative appeared to be more potent and selective than rimonabant.

21 analogs possessing either an alkyl amide or an alkyl hydrazide of variant lengths in position ثلاثة were synthesized. It was observed that affinity increases with increased carbon chain length up to five carbons. Also the amide analogs exhibited higher affinity than hydrazide analogs. However, none of these analogs possessed significantly greater affinity than rimonabant but nevertheless, they were slightly more selective than rimonabant for the CB₁ receptor over the CB₂ receptor.

Several attempts have been made to increase the affinity of the diarylpyrazole derivatives by rigidifying the structure of rimonabant. In terms of the general pharmacophore model the units A, B and/or C are connected by additional bonds leading to rigid molecules. For example the condensed polycyclic pyrazole NESS-0327 showed 5000 times more affinity for the CB₁ receptor than rimonabant. However, this compound possesses a poor central bioavailability.

Another compound, the indazole derivative O-1248, can be regarded as an analog of rimonabant wherein its 5-aryl group is fused to the pyrazole moiety. However, this structural modification resulted in a 67-fold decrease in CB₁ receptor affinity.

These diarylpyrazole derivatives of rimonabant are summarized in Table 1.

Other derivatives

Structurally different from the 1,5-diarylpyrazoles are the chemical series of the 3,4-diarylpyrazolines. Within this series is SLV-319 (ibipinabant), a potent CB₁ antagonist which is about 1000-fold more selective for CB₁ compared with CB₂ and displays in vivo activity similar to rimonabant.

Another approach used to develop analogs of rimonabant was to replace central pyrazole ring by another heterocycle. An example of this approach are 4,5-diarylimidazoles and 1,5-diarylpyrrole-3-carboxamides.

A large number of fused bicyclic derivatives of diaryl-pyrazole and imidazoles have been reported. An example of these is a purine derivative where a pyrimidine ring is fused to an imidazole ring.Otenabant (CP-945,598) is an example of a fused bicyclic derivative developed by Pfizer.

Several research groups have studied six-membered ring pyrazole bioisosteres. For example one 2,3-diarylpyridine derivative was shown to be potent and selective CB₁ inverse agonist. The structure of this compound demonstrates the possibility that the amide moiety of rimonabant could be split into a lipophilic (benzyloxy) and a polar (nitrile) functionality. Other six-membered ring analogs are for example pyrimidines and pyrazines.

In addition to the five and six-membered ring analogs there are other cyclic derivatives such as the azetidines. One example is the methylsulfonamide azetidine derivative which has a 1,1-diaryl group that mimics the 1,5-diaryl moiety of the diarylpyrazoles. The sulfonyl group serves as a hydrogen bond acceptor. The 1,1-diaryl group is also present in derivatives such as the benzodioxoles and hydantoins.

Acyclic analogs have also been reported. These analogs contain a 1,2-diaryl motif which corresponds to the 1,5-diaryl substituents of rimonabant. An example of an acyclic analog is taranabant (MK-0364) developed by Merck.

Representatives of these analogs are summarized in Table 2.

Current status

Rimonabant (Acomplia) has been approved in the European Union (EU) since June 2006 for the treatment of obesity. On 23^rd of October 2008 the European Medicines Agency (EMEA) has recommended the suspension of the marketing authorization across the EU for Acomplia from Sanofi-Aventis based on the risk of serious psychiatric disorders. On 5^th of November 2008 Sanofi-Aventis announced discontinuation of rimonabant clinical development program.

Sanofi-Aventis has also discontinued development of surinabant (SR147778), a CB₁ receptor antagonist for smoking cessation (31^st of October 2008).

Merck has stated in its press release on 2^nd of October 2008 that they will not seek regulatory approval for taranabant (MK-0364) to treat obesity and will discontinue its Phase III clinical development program. Data from Phase III clinical trial showed that greater efficacy and more adverse effects were associated with the higher doses of taranabant and it was determined that the overall profile of taranabant does not support further development for obesity.

Another pharmaceutical company, Pfizer, terminated the Phase III development program for its obesity compound otenabant (CP-945,598), a selective antagonist of the CB₁ receptor. According to Pfizer their decision was based on changing regulatory perspectives on the risk/benefit profile of the CB₁ class and likely new regulatory requirements for approval.

انظر أيضاً

• Cannabinoid receptor type 1
• Cannabinoid receptor
• Cannabinoids
• Endocannabinoid system
• Rimonabant

References