ITNA20090026A1 - NOP RECEPTOR AGONISTS AND THEIR THERAPEUTIC USES - Google Patents
NOP RECEPTOR AGONISTS AND THEIR THERAPEUTIC USES Download PDFInfo
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- ITNA20090026A1 ITNA20090026A1 IT000026A ITNA20090026A ITNA20090026A1 IT NA20090026 A1 ITNA20090026 A1 IT NA20090026A1 IT 000026 A IT000026 A IT 000026A IT NA20090026 A ITNA20090026 A IT NA20090026A IT NA20090026 A1 ITNA20090026 A1 IT NA20090026A1
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- ufp
- agonists
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- nop
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
DESCRIZIONE dell’invenzione avente per TITOLO: “Agonisti del recettore NOP e loro usi terapeutici”. DESCRIPTION of the invention with TITLE: "NOP receptor agonists and their therapeutic uses".
INTRODUZIONE La presente invenzione riguarda l’uso di composti in grado di attivare i recettori NOP al fine di ottenere preparazioni farmaceutiche utili per il trattamento dell’asma allergico e delle patologie clinicamente correlate. I composti utilizzabili secondo l’invenzione possono essere peptidi, derivati peptidici o molecole non-peptidiche, con proprietà di agonisti o agonisti parziali dei recettori NOP. Tali composti possono essere utilizzati in combinazione con altre sostanze attive usate nella terapia dell’asma allergico. L’asma è una malattia infiammatoria cronica delle vie aeree ad eziopatogenesi multifattoriale, nella quale svolgono un ruolo centrale cellule immunocompetenti, infiammatorie e mediatori da esse rilasciati. L’infiammazione cronica determina un aumento della responsi vità bronchiale (1) che, a sua volta, causa episodi ricorrenti di dispnea, respiro sibilante, senso di costrizione toracica e tosse, sintomi di solito associati ad una broncoostruzione variabile, spesso reversibile spontaneamente o col trattamento farmacologico. La persistenza della flogosi, qualora non sufficientemente controllata, può portare ad un rimodellamento delle vie aeree, ovvero ad una serie di alterazioni anatomiche, che rendono l'ostruzione parzialmente irreversibile. All’induzione ed all’evoluzione della malattia asmatica, che spesso inizia durante l’infanzia, contribuiscono sia fattori genetici (atopia) (2, 3) che fattori ambientali (virus, allergeni e esposizione occupazionale) (4, 5, 6, 7). L’asma bronchiale viene definito allergico se, alla diagnosi, si evidenzia una sensibilizzazione IgE-mediata verso uno o più allergeni, che agiscono inducendo ostruzione bronchiale in maniera specifica, ossia attivando in soggetti geneticamente predisposti eventi flogistici in conseguenza dell’interazione allergene-anticorpo (8). Per molti anni si è ritenuto, che infiltrazione cellulare di eosinofili e neutrofili, degranulazione di mastociti, perdita dell’ integrità delle strutture epiteliali, ostruzione mucosa del lume bronchiale, iperplasia ed ipertrofìa della muscolatura liscia bronchiale fossero una caratteristica peculiare della forma grave e non delle altre forme d’asma, specie dell’asma allergico che restava caratterizzata solo da broncospasmo, edema ed ipersecrezione mucosa (9). Al contrario, recentemente, studi effettuati sul lavaggio broncoalveolare (BAL), biopsie bronchiali ed espettorato indotto di soggetti con asma anche di grado lieve, hanno evidenziato la presenza di lesioni della parete delle vie aeree, conseguenti ad un processo flogistico (10), caratterizzato dalla presenza di citochine e chemochine proinfiammatorie (11). Nei soggetti sensibili, la malattia asmatica allergica è sempre conseguenza di fenomeni di sensibilizzazione e si sviluppa in due fasi: una immediata ed una ritardata. La sintesi delle IgE è consequenziale all’incontro dell’ antigene inalato con le cellule dendritiche delle vie aeree. Queste migrano, quindi, a livello dei linfonodi dove processano e presentano l’antigene ai linfociti T helper (ThO) (12), che a livello delle vie aeree sono presenti in due classi fenotipiche: i Th di classe 1 (Thl), che secernono IL-2 e interferone gamma (INF-γ), essenziali per i meccanismi di difesa cellulare, ed i Th di classe 2 (Th2), che attivati secernono citochine responsabili della flogosi allergica (IL-3, IL-4, IL-5, IL-9, EL-I3, GM-CSF) (13,14,15). I linfociti Th2, infatti, sono in grado di indurre ed amplificare sia l’iperproduzione di IgE, sia il coinvolgimento di eosinofili, mastociti, basofili e macrofagi (13,14,15). Le IgE così prodotte raggiungono la mucosa delle vie aeree ed ivi si legano a recettori specifici, presenti sui mastociti. Tale legame rappresenta il vero processo di sensibilizzazione che, in presenza di successive esposizioni all’antigene (16), darà luogo alle due fasi della reazione infiammatoria acuta. Clinicamente la fase precoce si risolve entro 1 ora ed è seguita da un periodo asintomatico, durante il quale le citochine e i mediatori formati durante la reazione di fase precoce richiamano i leucociti nei tessuti ed inducono una maggiore attivazione dei linfociti Th2. La citochina che svolge un ruolo più significativo in questo processo è l’IL-5 che, secreta da mastociti, eosinofili e linfociti, stimola l’attivazione degli eosinofili (17). Gli eosinofili così attivati lasciano il midollo osseo, e mediante il circolo ematico raggiungono le vie aeree (18,19), dove rilasciano il contenuto dei granuli responsabili del danno a livello della parete delle vie aeree (20,21). Questa reazione ritardata si manifesta clinicamente con infiammazione delle vie aeree, broncocostrizione e iperresponsività bronchiale (9). Per quanto riguarda la terapia dell’asma non esiste oggi alcun trattamento risolutivo. Esistono tuttavia numerosi ed efficaci trattamenti in grado di curare l'asma o di controllare i sintomi: farmaci sintomatici, efficaci nel risolvere la broncocostrizione (fc-agonisti), e farmaci specifici mirati suirinfìammazione e sulla broncoreattività (corticosteroidi e cromoni). I più potenti antinfiammatori disponibili per il trattamento dell’asma sono i glucocorticoidi. La loro efficacia è determinata da molteplici fattori: diminuzione della attivazione e del reclutamento delle cellule infiammatorie, riduzione della permeabilità vascolare, riduzione della produzione di muco, potenziamento della risposta ai farmaci fo-adrenergici. I farmaci più utilizzati nella profilassi dell’asma lieve-moderato sono i cromoni, che rendono la mucosa dell'apparato respiratorio meno reattiva nei confronti dell'allergene. Il trattamento va iniziato prima della possibile esposizione agli allergeni. Non assorbiti per via gastrointestinale e quindi non utilizzabili in preparazioni orali, i cromoni, nell’asma bronchiale, possono essere assunti esclusivamente per via inalatoria. Alla metà degli anno ’90 è stato identificato un nuovo peptide endogeno, denominato nocicettina/orfanina (N/OFQ) (22,23) che, pur appartenendo alla famiglia dei peptidi oppioidi, lega un recettore, denominato NOP, diverso dai classici recettori mu, delta e kappa (ora denominati MOP, DOP e KOP), secondo le indicazioni della IUPHAR) (24). Il recettore NOP mostra elevata affinità per N/OFQ, ma non per i classici ligandi oppioidi ed è ampiamente diffuso nel sistema nervoso centrale e periferico, come pure in altri sistemi o apparati (genitourinario, cardiovascolare e respiratorio), dove può essere espresso anche su cellule non neuronali. Studi condotti sull’attività biologica degli agonisti dei recettori NOP (25,26,27), hanno permesso di dimostrare che la N/OFQ: 1) esercita attività pro-nocicettiva (riduce la soglia del dolore) o anti-nocicettiva, a seconda che venga somministrato in siti sovra spinali o spinali; 2) produce effetti ansiolitici (mimati dagli agonisti non peptidici dei recettori NOP somministrati per via sistemica); riduce l’attività locomotoria; 4) aumenta l’assunzione di cibo. Inoltre, 5) produce effetti sul sistema renale (aumenta la diuresi quando somministrato per via endovenosa o i.c.v ); 6) cardiovascolare (ipotensione e bradicardia dopo somministrazione endovenosa); 7) gastrointestinale (effetti opposti di rilasciamento e contrazione a seconda della zona considerata); 8) respiratorio (inibizione del riflesso della tosse per attivazione delle fibre sensoriali afferenti).La farmacologia del sistema N/OFQ/ recettore NOP può attualmente contare su agonisti selettivi sia di natura peptidica quali [(pF)Phe<4>Aib<7>Arg<14>Lys<15>]N/OFQ-NH2(UFP-112) (28) e [(pF)Phe<4>,Arg<l4>,Lys<15>]N/OFQ-NH2(UFP-102) (29) sia non-peptidica quali l-[l-(l-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole (MCOPPB) (30); -[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510) (31); 2-(3,5-dimethylpiperazin-l-yl)-l-[l-(lmethylcyclooctyl)piperidin-4-yI]-lH-benzimidazole (PCPB) (32), [(lS,3aS)-8- (2,3,3a,4,5, 6-hexahydro-lH-phenalen-l-yl)-l-phenyl-l,3,8-triaza- spiro[4. 5]decan-4-one] (Ro 64-6198) (33). Ai fini della farmacologia del sistema N/OFQ/ recettore NOP assumono grande importanza anche gli antagonisti selettivi, anch’essi sia di natura peptidica quali [Nphe<1>, Arg<14>, Lys<15>] N/OFQ (1-13)NH2(UFP-101) (34) e [Nphe<1>] N/OFQ (1-13)NH2(35) sia nonpeptidica quali J-l 13397 (1-[(3R, 4R)-1- ciclooctilmetil-3-idrossimetil-4-piperidil]-3-etil-l,3-diidro-2H-benzimidazol-2-one (36,37), JTC-801 (N-(4-amino-2-metilchinolin-6-il)-2-(4-etilfenossimetil)benzamide cloridrato (38) INTRODUCTION The present invention relates to the use of compounds capable of activating NOP receptors in order to obtain pharmaceutical preparations useful for the treatment of allergic asthma and clinically related diseases. The compounds that can be used according to the invention can be peptides, peptide derivatives or non-peptide molecules, with properties of agonists or partial agonists of NOP receptors. These compounds can be used in combination with other active substances used in the treatment of allergic asthma. Asthma is a chronic inflammatory disease of the airways with multifactorial etiopathogenesis, in which immunocompetent and inflammatory cells and mediators released by them play a central role. Chronic inflammation causes increased bronchial responsiveness (1) which, in turn, causes recurrent episodes of dyspnoea, wheezing, chest tightness and cough, symptoms usually associated with variable bronchial obstruction, often reversible spontaneously or with Pharmacological treatment. The persistence of inflammation, if not sufficiently controlled, can lead to a remodeling of the airways, or to a series of anatomical alterations, which make the obstruction partially irreversible. Genetic factors (atopy) (2, 3) and environmental factors (viruses, allergens and occupational exposure) (4, 5, 6, 7) contribute to the induction and evolution of asthmatic disease, which often begins in childhood. ). Bronchial asthma is defined as allergic if, at diagnosis, an IgE-mediated sensitization towards one or more allergens is highlighted, which act by inducing bronchial obstruction in a specific way, i.e. by activating inflammatory events in genetically predisposed subjects as a consequence of the allergen-antibody interaction. (8). For many years it was believed that cellular infiltration of eosinophils and neutrophils, degranulation of mast cells, loss of integrity of the epithelial structures, mucosal obstruction of the bronchial lumen, hyperplasia and hypertrophy of the bronchial smooth muscles were a peculiar characteristic of the severe form and not of the other forms of asthma, especially allergic asthma which remained characterized only by bronchospasm, edema and mucous hypersecretion (9). On the contrary, recently, studies carried out on bronchoalveolar lavage (BAL), bronchial biopsies and induced sputum of subjects with even mild asthma, have shown the presence of lesions of the airway wall, consequent to an inflammatory process (10), characterized by the presence of proinflammatory cytokines and chemokines (11). In sensitive subjects, allergic asthmatic disease is always a consequence of sensitization phenomena and develops in two phases: one immediate and one delayed. The synthesis of IgE is consequential to the meeting of the inhaled antigen with the dendritic cells of the airways. These migrate, therefore, to the level of the lymph nodes where they process and present the antigen to the T helper lymphocytes (ThO) (12), which at the level of the airways are present in two phenotypic classes: the Th class 1 (Thl), which secrete IL-2 and interferon gamma (INF-γ), essential for cellular defense mechanisms, and the Th class 2 (Th2), which when activated secrete cytokines responsible for allergic inflammation (IL-3, IL-4, IL- 5, IL-9, EL-I3, GM-CSF) (13,14,15). In fact, Th2 lymphocytes are able to induce and amplify both the hyperproduction of IgE and the involvement of eosinophils, mast cells, basophils and macrophages (13,14,15). The IgE thus produced reach the mucosa of the airways and there they bind to specific receptors, present on mast cells. This link represents the true sensitization process which, in the presence of subsequent exposure to the antigen (16), will give rise to the two phases of the acute inflammatory reaction. Clinically, the early phase resolves within 1 hour and is followed by an asymptomatic period, during which the cytokines and mediators formed during the early phase reaction recall leukocytes in the tissues and induce greater activation of Th2 lymphocytes. The cytokine that plays a more significant role in this process is IL-5 which, secreted by mast cells, eosinophils and lymphocytes, stimulates the activation of eosinophils (17). The activated eosinophils leave the bone marrow, and through the blood circulation reach the airways (18,19), where they release the contents of the granules responsible for the damage to the airway wall (20,21). This delayed reaction manifests itself clinically with airway inflammation, bronchoconstriction and bronchial hyperresponsiveness (9). As far as asthma therapy is concerned, there is currently no definitive treatment. However, there are numerous and effective treatments capable of curing asthma or controlling symptoms: symptomatic drugs, effective in resolving bronchoconstriction (FC-agonists), and specific drugs aimed at inflammation and bronchoreactivity (corticosteroids and chromones). The most powerful anti-inflammatories available for the treatment of asthma are glucocorticoids. Their effectiveness is determined by multiple factors: decreased activation and recruitment of inflammatory cells, reduced vascular permeability, reduced mucus production, enhanced response to phadrenergic drugs. The drugs most used in the prophylaxis of mild-moderate asthma are chromones, which make the mucosa of the respiratory system less reactive towards the allergen. Treatment should be started before possible exposure to allergens. Not absorbed via the gastrointestinal tract and therefore not usable in oral preparations, chromones in bronchial asthma can only be taken by inhalation. In the mid-1990s a new endogenous peptide was identified, called nociceptin / orphanine (N / OFQ) (22,23) which, although belonging to the family of opioid peptides, binds a receptor, called NOP, different from the classic mu receptors. , delta and kappa (now called MOP, DOP and LAD), according to the indications of the IUPHAR) (24). The NOP receptor shows high affinity for N / OFQ, but not for the classic opioid ligands and is widely distributed in the central and peripheral nervous system, as well as in other systems or systems (genitourinary, cardiovascular and respiratory), where it can also be expressed on non-neuronal cells. Studies conducted on the biological activity of NOP receptor agonists (25,26,27), have shown that the N / OFQ: 1) exerts pro-nociceptive (reduces the pain threshold) or anti-nociceptive activity, depending on that it is administered to supra-spinal or spinal sites; 2) produces anxiolytic effects (mimicked by non-peptide agonists of NOP receptors administered systemically); reduces locomotor activity; 4) increases food intake. In addition, 5) produces effects on the renal system (increases diuresis when administered intravenously or i.c.v); 6) cardiovascular (hypotension and bradycardia after intravenous administration); 7) gastrointestinal (opposite effects of relaxation and contraction depending on the area considered); 8) respiratory (inhibition of the cough reflex by activation of the afferent sensory fibers). The pharmacology of the N / OFQ / NOP receptor system can currently rely on selective agonists of both peptide nature such as [(pF) Phe <4> Aib <7> Arg <14> Lys <15>] N / OFQ-NH2 (UFP-112) (28) and [(pF) Phe <4>, Arg <l4>, Lys <15>] N / OFQ-NH2 (UFP- 102) (29) and non-peptide such as 1- [1- (1-methylcyclooctyl) -4-piperidinyl] -2 - [(3R) -3-piperidinyl] -lH-benzimidazole (MCOPPB) (30); - [bis (2-methylphenyl) -methyl] -3-phenyl-8-azabicyclo [3.2.1] octan-3-ol (SCH 221510) (31); 2- (3,5-dimethylpiperazin-l-yl) -l- [l- (lmethylcyclooctyl) piperidin-4-yI] -lH-benzimidazole (PCPB) (32), [(lS, 3aS) -8- (2 , 3,3a, 4,5, 6-hexahydro-1H-phenalen-1-yl) -l-phenyl-1, 3,8-triaza-spiro [4. 5] decan-4-one] (Ro 64-6198) (33). For the pharmacology of the N / OFQ / NOP receptor system, selective antagonists are also of great importance, also both of peptide nature such as [Nphe <1>, Arg <14>, Lys <15>] N / OFQ (1- 13) NH2 (UFP-101) (34) and [Nphe <1>] N / OFQ (1-13) NH2 (35) both nonpeptide such as J-1 13397 (1 - [(3R, 4R) -1- cyclooctylmethyl-3 -hydroxymethyl-4-piperidyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (36,37), JTC-801 (N- (4-amino-2-methylquinolin-6-yl) -2- (4-ethylphenoxymethyl) benzamide hydrochloride (38)
e(-)-cis-l-methyl-7-[[4-(2,6-dichlorophenyl)viperidi-l-yl]methyl]-6,7,8,9-tetrahydro-5H benzocycIohepten-5-ol (SB612111) (39). and (-) - cis-1-methyl-7 - [[4- (2,6-dichlorophenyl) viperidi-1-yl] methyl] -6,7,8,9-tetrahydro-5H benzocycIohepten-5-ol ( SB612111) (39).
DESCRIZIONE DELL'INVENZIONE Le azioni farmacologiche della N/OFQ sono risultate rilevanti per la fisiologia delle vie respiratorie, il che è probabilmente dovuto alla presenza di immunoreattività alla N/OFQ nelle fibre nervose delle vie respiratorie e ai trascritti del gene per il recettore NOP nei gangli giugulari (40,41). Numerosi sono, infatti, i lavori che documentano una capacità della N/OFQ di influenzare la fisiologia delle vie aeree mediante la modulazione colinergica e tachichinergica. Pertanto, costituisce oggetto della presente invenzione l’utilizzo di composti in grado di attivare i recettori NOP in mammiferi, preferibilmente nell’uomo, per la preparazione di medicamenti utili al trattamento di patologie respiratorie, in particolare su base infiammatoria allergica, come l’asma bronchiale allergico. Tali composti possono essere peptidi, pseudo-peptidi (peptide-like), peptidomimetici, peptido-derivati oppure molecole non peptidiche. Senza limitare in alcun modo l’invenzione, si riportano i seguenti composti, agonisti dei recettori NOP, e i relativi riferimenti bibliografici e/o brevettuali, in cui viene fornita la loro preparazione e modalità d’uso e applicazione, qui interamente incorporati per riferimento. DESCRIPTION OF THE INVENTION Pharmacological actions of N / OFQ were found to be relevant to respiratory physiology, which is likely due to the presence of N / OFQ immunoreactivity in respiratory nerve fibers and NOP receptor gene transcripts in respiratory tract nerve fibers. jugular ganglia (40,41). In fact, there are numerous works documenting the ability of the N / OFQ to influence the physiology of the airways through cholinergic and tachykinergic modulation. Therefore, the object of the present invention is the use of compounds capable of activating NOP receptors in mammals, preferably in humans, for the preparation of medicaments useful for the treatment of respiratory diseases, in particular on an allergic inflammatory basis, such as asthma. allergic bronchial. Such compounds can be peptides, pseudo-peptides (peptide-like), peptidomimetics, peptide-derivatives or non-peptide molecules. Without limiting the invention in any way, the following compounds, agonists of NOP receptors, and the related bibliographic and / or patent references are reported, in which their preparation and methods of use and application are provided, fully incorporated herein by reference.
Agonisti peptidici: Peptide agonists:
Agonisti non peptidici: Non-peptide agonists:
Agonisti parziali: Partial agonists:
Secondo l’invenzione, la molecola preferita è il derivato peptidico (pF)Phe<4>Aib<7>Arg<14>Lys<15>]N/OFQ-NH2. Per 1 ’uso in terapia, i composti saranno formulati con veicoli ed eccipienti farmaceuticamente accettabili. Le forme farmaceutiche, il dosaggio, le vie e modalità di somministrazione dipenderanno principalmente dalla natura chimica del principio attivo, dalle sue caratteristiche farmacocinetiche e dal profilo di attività farmacologica e, ovviamente dallo stato di gravità della patologia. According to the invention, the preferred molecule is the peptide derivative (pF) Phe <4> Aib <7> Arg <14> Lys <15>] N / OFQ-NH2. For use in therapy, the compounds will be formulated with pharmaceutically acceptable vehicles and excipients. The pharmaceutical forms, the dosage, the routes and methods of administration will depend mainly on the chemical nature of the active principle, on its pharmacokinetic characteristics and on the pharmacological activity profile and, obviously, on the severity of the pathology.
RISULTATI SPERIMENTALI EXPERIMENTAL RESULTS
1. Valutazione ex vivo della modulazione del recettore NOP sulla reattività bronchiale di topi naive e sensibilizzati. 1. Ex vivo evaluation of NOP receptor modulation on bronchial reactivity of naive and sensitized mice.
1.1 Trattamento i.p. con agonisti e antagonisti NOP 1.1 Treatment i.p. with NOP agonists and antagonists
Vengono utilizzati topi del ceppo Balb/C di 9-12 settimane. Gli animali sono stabulati in ambiente climatizzato a temperatura costante di 21-23°C e 50-60% U.R., con cicli di lucebuio di 12 ore, e con acqua e cibo sempre disponibili. Gli animali sono divisi in due gruppi: 9-12 week old Balb / C mice are used. The animals are housed in an air-conditioned environment at a constant temperature of 21-23 ° C and 50-60% R.H., with 12-hour light and dark cycles, and with water and food always available. Animals are divided into two groups:
a) sensibilizzati alFovalbumina; b) naive a) sensitized to ovalbumin; b) naive
In particolare i topi, vengono sottoposti ai giorni 1 e 8 ad un’iniezione sottocute di 0.4 mi di una soluzione salina sterile di 10 pg OVA adsorbiti su 3.3 mg di gel di alluminio idrossido (sensibilizzati), o al solo veicolo (naive). Un gruppo di animali (sensibilizzati e naive), ai giorni 1 e 8 vengono trattati con ΙΟΟμΙ di una soluzione contraente l’ agoni sta UFP-112 (Ο.ΙμΜ) o l’antagonista UFP-101 (ΙμΜ) o il solo veicolo, 30 min prima del trattamento o con l’allergene o con il veicolo. Al giorno 21 si procede alle valutazioni funzionali effettuando una curva dose-risposta all’ ACh. I topi sono alloggiati in una camera di resina acrilica costituita da un’ intercapedine che permette l’entrata di acqua distillata riscaldata in un bagnetto termostatico settato a 37° C. Tale camera è posizionata in modo da formare un angolo di circa 20 gradi con l’asse orizzontale: in tal modo, la parte superiore della camera (apici dei polmoni) risulta essere elevata di circa 1 cm sul piano verticale rispetto alla parte inferiore (basi dei polmoni). La camera, che funziona come gabbia toracica artificiale, è costruita in modo da consentire la chirurgia, la perfusione e la ventilazione del polmone di topo. Una volta anestetizzato l’animale con 160 mg/Kg di pentobarbitale sodico, si esegue un’incisione della pelle in senso caudo-craniale, si espone la trachea e la si intuba mediante un piccolo taglio. Si inserisce così la cannula all’interno della trachea, che risulta quindi collegata ad un pneumotacografo mediante un tubicino di silicone nel quale è inserita la cannula stessa, ed il polmone viene ventilato con una pressione positiva (90 respiri/min, 250-300μ1 tidal volume). A questo punto si apre l’addome, si rimuove il diaframma, ed il topo viene eparinizzato mediante iniezione di eparina intracardiaca. Dopo dissanguamento, mediante incisione della vena renale, si apre il torace e si fissano le due metà di quest’ultimo alla cameretta, in modo da esporre cuore e polmoni. Si incannula l’arteria polmonare, effettuando un piccolo taglio a livello del ventricolo destro, alla base deH’arteria, mediante una cannula di perfusione. Successivamente si effettua un secondo taglio sotto il ventricolo sinistro, dove viene inserita la seconda cannula che permette la fuoriuscita del perfusato. Chiudendo la camera e agendo su un’apposita pompa di scambio, si genera una pressione di ventilazione negativa oscillante tra -2 e -10 cm H20, in modo da avere un volume respiratorio di 200 pl.(NPV). I polmoni vengono perfusi, attraverso l’arteria polmonare, in modo continuo e costante, con un flusso (generato da una pompa peristaltica, Ismatec MS Regio) di 0,6 ml/min, (che corrisponde circa all’ 8% del flusso cardiaco del topo), in grado di generare una pressione arteriosa polmonare di 2-3 cm H20. Il buffer di perfusione (37° C) è costituito dal mezzo di coltura RPMI 1640, privato del rosso fenolo, e da albumina al 4% a basso contenuto di endotossine. La pressione toracica (camera artificiale) viene misurata grazie ad un trasduttore differenziale di pressione (Validyne DP 45-24), ed il flusso respiratorio mediante un pneumotacografo connesso ad un altro trasduttore differenziale di pressione (Validyne 45-15). L’aria che arriva ai polmoni viene umidificata da un apposito sistema, posizionato in prossimità della cannula tracheale. Si può monitorare continuamente la pressione arteriosa grazie ad un trasduttore di pressione (isotec Healthdyne) connesso alla cannula di perfusione dell’arteria polmonare. Tutti i dati vengono trasmessi a un computer e analizzati da un “software Polmonare” (Hugo Sachs Elektronik, March Hugstetten, Germany). Dopo l’intervento chirurgico, i polmoni vengono perfiisi e ventilati per circa 45 minuti, per registrare le funzioni polmonari basali. A questo punto si eseguono somministrazioni ripetute di acetilcolina (ACh ÌO^-IO^M) in modo da ottenere una curva dose-risposta. L’ACh induce una bronco-costrizione sia in topi naive che in quelli sensibilizzati aH’ovalbumina con un effetto massimo alla concentrazione di 10<~3>M. Il trattamento con l’agonista UFP-112 (Ο.ΙμΜ) o con l’antagonista UFP-101 (ΙμΜ) sono in grado, rispettivamente, di ridurre ed aumentare l’attività broncocontratturante dell’ACh, solo nei topi sensibilizzati all’OVA senza modificare in alcun modo la reattività nei topi naive (Fig i). In particular, mice are subjected on days 1 and 8 to a subcutaneous injection of 0.4 ml of a sterile saline solution of 10 pg OVA adsorbed on 3.3 mg of aluminum hydroxide gel (sensitized), or to the vehicle alone (naive). A group of animals (sensitized and naïve), on days 1 and 8 are treated with ΙΟΟμΙ of a UFP-112 contracting solution (Ο.ΙμΜ) or the antagonist UFP-101 (ΙμΜ) or the vehicle alone, 30 min before treatment either with the allergen or with the vehicle. On day 21, functional assessments are carried out by carrying out a dose-response curve to ACh. The mice are housed in an acrylic resin chamber consisting of a cavity that allows the entry of distilled water heated into a thermostatic bath set at 37 ° C. This chamber is positioned so as to form an angle of about 20 degrees with the 'horizontal axis: in this way, the upper part of the chamber (apexes of the lungs) is elevated by about 1 cm on the vertical plane with respect to the lower part (bases of the lungs). The chamber, which functions as an artificial rib cage, is constructed to allow for surgery, perfusion and ventilation of the mouse lung. Once the animal has been anesthetized with 160 mg / kg of sodium pentobarbital, a caudal-cranial skin incision is made, the trachea is exposed and intubated with a small cut. The cannula is thus inserted inside the trachea, which is then connected to a pneumotachograph by means of a silicone tube in which the cannula itself is inserted, and the lung is ventilated with a positive pressure (90 breaths / min, 250-300μ1 tidal volume). At this point the abdomen is opened, the diaphragm is removed, and the mouse is heparinized by injection of intracardiac heparin. After bleeding, by incision of the renal vein, the thorax is opened and the two halves of the latter are fixed to the bedroom, so as to expose the heart and lungs. The pulmonary artery is cannulated, making a small cut in the right ventricle, at the base of the artery, using a perfusion cannula. Subsequently, a second cut is made under the left ventricle, where the second cannula is inserted which allows the perfusate to escape. By closing the chamber and acting on a special exchange pump, a negative ventilation pressure oscillating between -2 and -10 cm H20 is generated, so as to have a respiratory volume of 200 pl. (NPV). The lungs are perfused, through the pulmonary artery, in a continuous and constant way, with a flow (generated by a peristaltic pump, Ismatec MS Regio) of 0.6 ml / min, (which corresponds to about 8% of the cardiac flow mouse), capable of generating a pulmonary arterial pressure of 2-3 cm H20. The perfusion buffer (37 ° C) consists of RPMI 1640 culture medium, deprived of phenol red, and 4% albumin with low endotoxin content. The thoracic pressure (artificial chamber) is measured thanks to a differential pressure transducer (Validyne DP 45-24), and the respiratory flow by means of a pneumotachometer connected to another differential pressure transducer (Validyne 45-15). The air that reaches the lungs is humidified by a special system, positioned near the tracheal cannula. Blood pressure can be continuously monitored thanks to a pressure transducer (isotec Healthdyne) connected to the pulmonary artery perfusion cannula. All data is transmitted to a computer and analyzed by a “Pulmonary software” (Hugo Sachs Elektronik, March Hugstetten, Germany). After surgery, the lungs are perfected and ventilated for about 45 minutes, to record the basal lung functions. At this point, repeated administrations of acetylcholine (ACh 10O ^ -IO ^ M) are carried out in order to obtain a dose-response curve. ACh induces a broncho-constriction both in naive mice and in those sensitized to H ovalbumin with a maximum effect at a concentration of 10 <~ 3> M. Treatment with the agonist UFP-112 (Ο.ΙμΜ) or with the antagonist UFP-101 (ΙμΜ) are able, respectively, to reduce and increase the bronchocontracting activity of ACh, only in mice sensitized to OVA. without modifying in any way the reactivity in naive mice (Fig i).
1.2 Trattamento mediante pompe osmotiche con agonisti ed antagonisti del recettore NOP 1.2 Treatment by osmotic pumps with agonists and antagonists of the NOP receptor
Topi del ceppo Balb/C (n=8), di 9-12 settimane, sono trattati con pompe osmotiche (Alzet) caricate con ΙΟΟμΙ di una soluzione contenente l’agonista UFP112 (ΙμΜ) o l’antagonista UFP 101 (Ο.ΙμΜ) o soluzione salina. Una singola pompa eroga 0,5pl/hr garantendo un’ infusione continua per una settimana. Per rimpianto delle pompe gli animali vengono anestetizzati con ketamina-xilazina (100mg/Kg-10mg/Kg). Successivamente viene effettuata un’incisione a livello dorsale per consentire l’inserimento sotto cute della pompa osmotica Un gruppo di animali è sensibilizzato all’ovalbumina 24h dopo l’inserimento delle pompe, seguendo lo stesso protocollo di sensibilizzazione già descritto. Al giorno 21 si esegue la valutazione dei parametri funzionale utilizzando lo stesso protocollo sperimentale già descritto. Come si può osservare dalla figura 2B il trattamento con pompe osmotiche caricate con UFP-112 indica una significativa riduzione della responsività bronchiale all<’>ACh rispetto ai topi trattati con pompe caricate con UFP-101 e salina. Nella figura 2 A si nota, invece, come gli stessi trattamenti in topi naive non apportano alcuna modifica della responsività bronchiale all’ACh. Mice of the Balb / C strain (n = 8), aged 9-12 weeks, are treated with osmotic pumps (Alzet) loaded with ΙΟΟμΙ of a solution containing the agonist UFP112 (ΙμΜ) or the antagonist UFP 101 (Ο.ΙμΜ ) or saline solution. A single pump delivers 0.5pl / hr ensuring a continuous infusion for one week. To regret the pumps, the animals are anesthetized with ketamine-xylazine (100mg / Kg-10mg / Kg). Subsequently, a dorsal incision is made to allow the osmotic pump to be inserted under the skin. A group of animals is sensitized to ovalbumin 24 hours after the insertion of the pumps, following the same sensitization protocol already described. On day 21 the evaluation of the functional parameters is performed using the same experimental protocol already described. As can be seen from Figure 2B, treatment with osmotic pumps loaded with UFP-112 indicates a significant reduction in bronchial responsiveness to ACh compared to mice treated with pumps loaded with UFP-101 and saline. In Figure 2 A, however, it can be seen that the same treatments in naive mice do not bring about any change in bronchial responsiveness to ACh.
1.3 Trattamento mediante somministrazione aerosolica con agonisti ed antagonisti del recettore NOP 1.3 Treatment by aerosol administration with NOP receptor agonists and antagonists
I topi, vengono sottoposti ai giorni 1 e 8 ad un’iniezione sottocute di 0.4 mi di una soluzione salina sterile di 10 pg OVA adsorbiti su 3.3 mg di gel di alluminio idrossido (sensibilizzati), o al solo veicolo (naive). Un gruppo di animali, è sottoposto a 5 aerosol consecutivi della durata di 4 min per un totale di 20 minuti per S giorni consecutivi con agoni sta (UFP-112 Ο,ΟΙμΜ/ml) o con antagonista (UFP-101 0,1 pM/ml) o con soluzione salina. Il primo giorno di trattamento aerosolico inizia tre giorni prima della sensibilizzazione allergenica. Le concentrazioni deU’agonista o dell’antagonista risultano 10 volte inferiori a quelle utilizzate nei trattamenti i.p. e con pompe. Al giorno 21 si esegue la valutazione funzionale mediante l’applicazione del già descritto protocollo sperimentale. Gli animali esposti all’aerosol con UFP-1 12 mostrano una significativa riduzione della responsività bronchiale all’ACh rispetto agli animali esposti all’aerosol con l’antagonista UFP-101 o con la soluzione salina. (Fig. 3). The mice are subjected on days 1 and 8 to a subcutaneous injection of 0.4 ml of a sterile saline solution of 10 pg OVA adsorbed on 3.3 mg of aluminum hydroxide gel (sensitized), or to the vehicle alone (naive). A group of animals is subjected to 5 consecutive aerosols lasting 4 min for a total of 20 minutes for S consecutive days with agonist (UFP-112 Ο, ΟΙμΜ / ml) or with antagonist (UFP-101 0.1 pM / ml) or with saline solution. The first day of aerosol treatment begins three days before allergenic sensitization. The concentrations of the agonist or antagonist are 10 times lower than those used in i.p. treatments and with pumps. On day 21, the functional assessment is performed by applying the previously described experimental protocol. Animals exposed to aerosol with UFP-1 12 show a significant reduction in bronchial responsiveness to ACh compared to animals exposed to aerosol with the antagonist UFP-101 or with saline. (Fig. 3).
2. Valutazione in vitro della modulazione del recettore NOP sulla reattività bronchiale di topi naive e sensibilizzati. 2. In vitro evaluation of the modulation of the NOP receptor on the bronchial reactivity of naïve and sensitized mice.
Gli animali (topi Balb/C, n=8) sono stati sensibilizzati seguendo lo stesso protocollo usato per gli studi ex- vivo e trattati mediante somministrazione i.p. con 100 μΐ di una soluzione contenente l’agonista UFP-112 (Ο.ΙμΜ) o l’antagonista UFP-101 (ΙμΜ) o di fisiologica prima della sensibilizzazione all’ovalbumina. Al giorno 21 gli animali sono sacrificati per permettere l’isolamento del tessuto bronchiale. Si procede con la rimozione del tessuto adiposo e connettivo e all’ottenimento di anelli bronchiali di 1-2 mm. In particolare gli anelli sono posti in bagnetti per organi isolati, contenenti soluzione di Krebs ossigenata (95% 02-5% C02) a 37°C e montati su un trasduttore di forza isometrico (type 7006; Ugo Basile, Comerio, Italy) connesso ad un Powerlab 800 (ADInstruments). Sono valutati gli effetti dell’ UFP-112 e UFP-101 sulla reattività bronchiale, effettuando una curva cumulativa concentrazione-risposta all’ ACh (IO<-9>- IO<-4>M). I dati in vitro, confermano l’andamento registrato ex-vivo, mostrando una capacità dell’ agonista e dell’antagonista di modificare la reattività all’ ACh solo nei topi sensibilizzati. (Fig.4B). Al contrario, in topi naive la modulazione del recettore NOP non modifica in alcun modo la reattività bronchiale (Fig.4A). The animals (Balb / C mice, n = 8) were sensitized following the same protocol used for the ex vivo studies and treated by i.p. with 100 μΐ of a solution containing the agonist UFP-112 (Ο.ΙμΜ) or the antagonist UFP-101 (ΙμΜ) or physiological before sensitization to ovalbumin. On day 21, the animals are sacrificed to allow the isolation of the bronchial tissue. We proceed with the removal of adipose and connective tissue and obtain bronchial rings of 1-2 mm. In particular, the rings are placed in baths for isolated organs, containing oxygenated Krebs solution (95% 02-5% C02) at 37 ° C and mounted on a connected isometric force transducer (type 7006; Ugo Basile, Comerio, Italy) to a Powerlab 800 (ADInstruments). The effects of UFP-112 and UFP-101 on bronchial reactivity are evaluated by carrying out a cumulative concentration-response curve to ACh (IO <-9> - IO <-4> M). The in vitro data confirm the trend recorded ex vivo, showing an ability of the agonist and antagonist to modify the reactivity to ACh only in sensitized mice. (Fig.4B). On the contrary, in naive mice the modulation of the NOP receptor does not modify the bronchial reactivity in any way (Fig.4A).
3. Effetti della modulazione del recettore NOP sulla risposta infiammatoria polmonare. 3. Effects of NOP receptor modulation on pulmonary inflammatory response.
Gli animali (topi Balb/C, n=8) sono stati sensibilizzati seguendo lo stesso protocollo usato per gli studi ex-vivo e trattati mediante somministrazione i.p. con ΙΟΟμΙ dell’ agonista UFP-1 12 (0. ΙμΜ) o dell’antagonista UFP-101 (ΙμΜ) o di fisiologica prima della sensibilizzazione aH’ovalbumina. Al giorno 21 gli animali sono sottoposti a lavaggio bronco-alveolare. In particolare, i topi sono anestetizzati con ketamina-xilazina (100mg/Kg-10mg/Kg) per favorire l’esposizione della trachea e l’inserimento di un catetere. Si eseguono 3 iniezioni da 500μ1 di soluzione fisiologica. Durante ogni lavaggio viene aspirato il contenuto bronchiale, che successivamente viene aliquotato per consentire la valutazione cellulare e il dosaggio delle citochine. La vitalità cellulare è valutata con il test di esclusione al trypan blue, effettuando la conta totale mediante l’utilizzo di una camera Burker. Come si evince dalla figura 5 A il trattamento con agonista UFP-112 determina una significativa riduzione della popolazione cellulare rispetto all’antagonista UFP-101. Il dosaggio delle citochine prò ed anti-infiammatorie si esegue mediante utilizzo di kit ELISA (BioRad). Nella figura 5B è mostrato come il trattamento con agonista IJFP-l 12 è in grado di ridurre significativamente i livelli delle IL-2, IL-4 e IL- 17. L’antagonista UFP-101 al contrario è in grado di aumentare in maniera significativa IL-17, senza indurre alcuna modifica dell’IL-2 e IL-4. The animals (Balb / C mice, n = 8) were sensitized following the same protocol used for the ex vivo studies and treated by i.p. with ΙΟΟμΙ of the agonist UFP-1 12 (0. ΙμΜ) or of the antagonist UFP-101 (ΙμΜ) or physiological before sensitization to H ovalbumin. On day 21, the animals underwent bronchoalveolar lavage. In particular, the mice are anesthetized with ketamine-xylazine (100mg / Kg-10mg / Kg) to favor the exposure of the trachea and the insertion of a catheter. Three 500μ1 injections of physiological solution are performed. During each wash the bronchial contents are aspirated, which is subsequently aliquoted to allow the cell evaluation and the dosage of the cytokines. Cell viability is assessed with the trypan blue exclusion test, by carrying out the total count using a Burker chamber. As can be seen from Figure 5 A, treatment with the UFP-112 agonist results in a significant reduction in the cell population compared to the UFP-101 antagonist. The dosage of pro and anti-inflammatory cytokines is performed by using an ELISA kit (BioRad). Figure 5B shows how treatment with an IJFP-1 12 agonist is able to significantly reduce the levels of IL-2, IL-4 and IL-17. The UFP-101 antagonist, on the contrary, is able to increase significantly significant IL-17, without inducing any modification of IL-2 and IL-4.
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