NOP RECEPTOR ANTAGONISTS FOR THE TREATMENT OF PARKINSON'S DISEASE
The present invention provides the use of compounds able to block or inhibit the NOP receptor for the preparation of medicaments for the treatment of Parkinson's disease and clinically related parkinsonisms. According to the invention, peptides, peptide-derivatives and non-peptide molecules can be used as antagonists or partial agonists at NOP receptors. The invention is also directed to combined preparations of NOP-receptor antagonists or partial agonists with different biologically-active substances, for the therapy of Parkinson's disease and clinically related disorders. BACKGROUND OF THE INVENTION Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder, clinically characterized by hypo/akinesia, rigidity, gait disturbance and resting tremor, often associated with mood changes (namely depression) and dementia. PD is typically a senile disease, although juvenile onset has been described. Etiology of PD is still unknown, although recent studies are in support of a multifactorial hypothesis, involving genetic, environmental and toxic- metabolic factors (Stocchi, 1998). Nevertheless, it is well recognized that the main biochemical alteration is represented by degeneration of dopamine (DA) releasing neurons located in the substantia nigra (SN) compacta, which is followed by denervation of target areas (mainly the striatum and the subthalamic nucleus) and plastic changes of DAergic (receptor up-regulation) and non-DAergic neuronal systems (e.g. glutamate releasing neurons; Hirsch et al., 2000; Chase and Oh, 2000). The treatment of PD (and partly of parkinsonisms) is presently based on pharmacological and neurosurgical therapy (Stocchi, 1998). Levodopa (L,3-4- dihydrohydroxyphenylalanine) still represents the gold standard of
symptomatic PD therapy (see Obeso et al., 2000). Nevertheless, chronic levodopa administration is invariably associated with appearance (within 5-10 years in about 80 % of patients) of motor complications that limit its clinical effectiveness and greatly reduce the quality of life of patients (Obeso et al., 2000). Another group of antiparkinsonian drugs is represented by D2 dopaminergic agonists that, unlike levodopa, act by directly stimulating D2 receptors, without the need of enzymatic conversion and independently from integrity of DAergic pathways. Dopaminomimetics, however, display more adverse effects than levodopa, especially at the peripheral level. Anticholinergic drugs (namely, muscarinic receptor blockers) show poor clinical effectiveness, being useful only in control of rigidity and, to a lesser extent, tremor. Also, they are not well tolerated. The monoamino-oxidase type B (MAOB) inhibitor selegiline and catecol-O-methyl-transferase (COMT) inhibitors entacapone and tolcapone are also clinically effective. In any case, both MAOB and COMT inhibitors are effective only in association with levodopa. Finally, the neurologist armamentarium is enriched by amantadine, which can be effective in the early phase of the disease. In addition to idiopathic PD, others clinically correlated hypokinetic syndromes have been described, which are characterized by rigidity, bradykinesia and paucity of movements, and thereby classified as parkinsonisms. These diseases have a different etiology, partly still unknown (primary parkinsonisms) and partly related (secondary parkinsonisms) to vascular accidents, trauma, infections and drugs (e.g. the well-known neurolep tic-induced parkinsonism). Unlike PD, these diseases are poorly responsive to DAergic drugs. Nevertheless, they are typically treated with conventional antiparkinsonian drugs, which, however, do not completely and satisfactorily reverse symptoms.
Therefore, it clearly emerges that the mainstay of PD therapy is still represented by chronic levodopa therapy, which is however burdened by progressive loss of clinical efficacy and onset of disabling side-effects. Thus, it appears crucial to develop novel antiparkinsonian drugs bearing equal or greater efficacy than levodopa and, in any case, less side-effects. In addition, it must be noted that all the above-mentioned drugs are able to reverse symptoms but not to slow the progression of the disease. Indeed, an effective neuroprotective therapy, able to prevent or slow degeneration of SN DA neurons, has not been developed yet. Finally, the need for new antiparkinsonian drugs is particularly urgent for management of parkinsonisms, which are poorly responsive to conventional drugs. In the mid '90s, a new peptide, termed nociceptin/orphanin FQ (N/OFQ; Meunier et al., 1995; Reinscheid et al., 1995) was identified. N/OFQ belongs to the opioid family, but interacts with a G-protein-coupled receptor (the NOP receptor) which differentiates from the 3 classical mu, kappa and delta opioid receptors (now re-named MOP, KOP and DOP according to recent IUPHAR recommendations; Cox et al., 2000). The NOP receptor, which shows high affinity for N/OFQ but no affinity for classical opioid ligands, is widely expressed in the central and peripheral nervous system, as well as in other systems (e.g. cardiovascular and genitourinary) where it can be expressed also by non neuronal cells. Studies focusing on the biological activity of NOP receptor agonists (for recent reviews see Calό et al., 2000; Mogil and Pasternak, 2001) have demonstrated that N/OFQ: i) induces hyperalgesia (i.e. reduces pain threshold) or analgesia, when administered supraspinally or spinally, respectively; ii) induces anxiolysis (mimicked by non-peptide NOP receptor agonists administered systemically); iii) reduces locomotor activity, iv) increases food assumption, v) affects the renal system (increases the diuresis when given i.v. or i.e. v.), vi) affects the cardiovascular system
(hypotension and bradycardia after i.v. administration, vii) affects the gastrointestinal system (relaxation and contraction, depending on the segment affected). The pharmacology of the N/OFQ-NOP receptor system can now take advantage of selective peptide antagonists such as [Nphe1]N/OFQ(l-13)NH2 (Calό et al., 2000) and UFP-101 ([Nphe1,Arg14, Lys15]N/OFQ(l-13)NH2; Calό et al., 2002) or non-peptide antagonists such as J-l 13397 (1-[(3R,4R)-1- cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-l ,3-dihydro- benzimidazol-2-one; Kawamoto et al., 1999; Ozaki et al., 2000) and JTC-801 ([N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride]; Shinkai et al., 2000; Yamada et al., 2002). These compounds have demonstrated strong antagonistic properties against the effects of NOP receptor agonists in several experimental tests in vitro and in vivo. In rodents in vivo, they also displayed primary effects opposite to those of the natural ligand N/OFQ, suggesting the existence of an endogenous N/OFQergic tone on some biological functions, such as food intake, where [Nρhe1]N/OFQ(l-13)NH2 induced anorexia (Polidori et al., 2000), or pain threshold, where i.e. . administration of [Nphe1]N/OFQ(l-13)NH2 and UFP- 101 induced analgesia (Calo et al., 2000). Moreover, i.c.v. administration of [NpheI]N/OFQ(l-13)NH2 and UFP-101 induced antidepressant-like effects (Redrobe et al., 2002; Gavioli et al., 2003). In addition to selective antagonists, non selective antagonists are also available, which block NOP receptors and also stimulate opioid receptors of the MOP type. Among these, the peptide III-BTD (Becker et al., 1999) and naloxone benzoylhydrazone (6- deoxy-6-benzoylhydrazido-N-allyl-14-hydroxydihydromorphinone; Gistrak et al., 1989; Dunnil et al., 1996). NOP receptor blockade can also be obtained with partial agonists, which prevent the effects of the endogenous agonist but retain some ability to activate the NOP receptor: among these compounds, the
pseudopeptide [Phe^(CH2-NH)Gly2]N/OFQ(l-13)NH2 (Guerrini et al., 1998) and the peptide analogues Ac-RYYRWKNH2 and Ac-RYYRIKNH2 (the latter being endowed with less primary agonist activity; Dooley et al., 1997). DESCRIPTION OF THE INVENTION NOP receptor antagonists or partial agonists have been proven to be pharmacologically active in PD animal models. In particular, clear antiparkinsonian effects in the rat made cataleptic with haloperidol and in the unilaterally 6-hydroxydopamine (6-OHDA) lesioned rat have been observed after intracerebral or systemic injections of these compounds. Results obtained from in vivo experiments clearly indicate that NOP receptor antagonists or partial agonists reduce symptoms and relieve from parkinsonism. Therefore, object of this invention is the use of compounds able to block or inhibit NOP receptors in mammals, preferably in humans, for the preparation of a medicament useful for treating Parkinson's disease and clinically related parkinsonisms. The compounds according to the invention include peptides, pseudopeptides (peptide-like), peptidomimetics. peptide-derivatives or non- peptide molecules, preferably the following NOP receptor antagonists or partial agonists, the pharmacological properties of which, as well as their chemical preparation and use/application, are described in detail in the corresponding literature and/or patent references, which are entirely incorporated by reference herein: 1. Peptide antagonists: [Nphe1]N/OFQ(l-13)NH2 (Calό et al., 2000); [Nphe!,Arg14,
Lys15]N/OFQ(l-13)NH2 (UFP-101 ; Calό et al., 2002); III-BTD (Ac-Arg- DCha-BTD-DArg-D(pCl)Phe-NH2) where BTD = (3S, 6S, 9R)-2-oxo-3- amino-7-thia-l-aza-bicyclo [4,3,0]nonan-9-carboxylic acid; Becker et al.,
1999). 2. Peptide partial agonists:
[PheV(CH2-NH)Gly2]N/OFQ(l-13)NH2 (Guerrini et al., 1998); Ac- RYYRWKNH2 and Ac-RYYRIKNH2 (Dooley et al., 1997); 3. Non-peptide antagonists: Naloxone benzoylhydrazone (6-deoxy-6~benzoylhydrazido~N-allyl- 14- hydroxydihydromorphinone); morphinan hydroxamic acid derivatives (EP
829481 e JP0053572). Spiropiperidinic compounds (EP-963985; EP-963987 and EP-970957), in particular antagonists obtained by simultaneously modifying the spiropiperidinic ring and the substituent on piperidinic nitrogen
(WO9929696). Spiropiperidinic compounds (WO0034280 e JP2000169476), in particular the benzimidazopiperidines (WO9854168), among which J-113397
(l-[(3R,4R)-l-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-l,3- dihydro-benzimidazol-2-one; Kawamoto et al., 1999; Ozaki et al., 2000) and further derivatives (WO0031061); piperidinic compounds (WO0014067 and
WO0027815); 4-6 diaminoquinolines (WO9948492), among which JTC-801 ([N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride]; Shinkai et al., 2000; Yamada et al., 2002);
4-oxoimidazoline-2-spiro nitrogenated compounds (WO 0196337). According to the invention, preferred peptide, pseudopeptide or peptide-like compounds are [Nphe1]N/OFQ(l-13)NH2, [Nphe^Arg 14,Lys15]N/OFQ(l-13)NH23 [Phe1i| CH2-NH)Gly2]N/OFQ(l-13)NH2, Ac- RYYRWKNH23 Ac-RYYRIKNH2 and Ac-Arg-DCha-BTD-DArg-D(pCl)Phe- NH2, where N/OFQ represents the nociceptin sequence (PheGlyGlyPheThrGlyAlaArgLysSerAlaArgLysLeuAlaAsnGln), BTD = (3S, 6S, 9R)-2-oxo-3-amino-7-thia-l-aza-bicyclo [4,3,0]nonan-9-carboxylic acid, Ψ represents the bond between two aminoacid residues and is preferably CH2NH. Among non peptide compounds, benzimidazopiperidinic antagonists, particularly the 1 -[(3R,4R)- 1 -cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]- 3-ethyl-l,3-dihydro-benzimidazol-2-one, 4-6 diaminoquinolines such as
[N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydro chloride], and naloxone benzoylhydrazone (6-deoxy-6- benzoylhydrazido-N-allyl-14-hydroxydihydromorphinone), are preferred. In the context of the present invention, the terms antagonists and partial agonist are used as in the common meaning, and indicate NOP receptor ligands which completely or partially prevent the effect of an agonist activating the same receptor. For therapeutical uses, the compounds presented herein will be formulated with vehicles and pharmaceutically acceptable excipients. Pharmaceutical preparations, dosage, routes and modalities of administration will depend on the chemical nature of the active compound (peptide, peptide- like or non peptide molecule), on its pharmacokinetic and pharmacological profile, on the disease to be cured, its severity, and the patient's general health conditions. Pharmaceutical formulations will preferably deliver an effective amount of active compound through the blood brain barrier, in particular in the brain areas affected by neurodegeneration. Moreover, according to the invention, the NOP receptor antagonists or partial agonists can be used in association with different pharmacologically-active substances such as levodopa/carbidopa and levodopa/benserazide, amantadine, bromocriptine or more in general with dopaminomimetics, antidepressants, anticholinergic compounds, MAO and COMT inhibitors. The therapeutic approach based on NOP receptor blockade or inhibition is particularly favourable since the antagonists or partial agonists: 1. act independently from the dopaminergic system, by blocking the action of an endogenous modulator (i.e. N/OFQ). Unlike levodopa, their clinical effectiveness does not fade over time due to DAergic neuron degeneration. Moreover, the use of an antagonist rather than an agonist, will prevent the development of receptor overactivation and chronic receptor down-regulation, which underlie acute toxicity of dopaminomimetics and
levodopa-induced dyskinesia. Moreover, the possibility to act on the N/OFQergic system opens novel possibilities for therapeutic interventions based on synergism with commercially available antiparkinsonian drugs. 2. have antidepressant properties (Redrobe et al., 2002; Gavioli et al., 2003), and PD is known to be associated with depression in about 30-40 % of parkinsonian patients. 3. have neuroprotective effects in some models of glutamate- mediated toxicity (Laudenbach et al., 2001). Indeed, increased glutamate release may, at least in part, underlie progressive degeneration of SN DAergic neurons. Thus, they can exert antiparkinsonian activity both at symptomatic and causal level. EXPERIMENTAL DATA Effects of [Nphe1 ,Arg14 ,Lys15]N/OFQ(l-13)NH2 (UFP-101) in the naϊve rat Sprague-Dawley rats weighing 300-350 g are used. Rats are anesthetised with isoflurane and placed on a stereotaxic apparatus. Deep anesthesia is maintained all throughout the experiment. After disclosing the skull, a hole in the parietal bone is made and a stainless-steel infusion cannula (15 mm length, 24 gauge) is implanted according to following stereotaxic coordinates (AP -5.5, ML -2.2, VD -7.3; Paxinos and Watson 1982), so that the tip lies 1 mm above the right SN reticula a (SNr). A stainless-steel speculum is then inserted into the cannula to avoid occlusion due to external material. The cannula is then fixed to the skull with metacrilic cement and anesthesia interrupted. Each animal is then placed in a single polycarbonate cage with free access to food and water. After surgery, the rat is manipulated and trained during daily session to remain in equilibrium on a rotating cilynder (Rotardod test; Rozas et al., 1997), until its performance becomes reproducible. The experiment is performed seven days after surgery. The animal is first tested on the rotarod (control session). Forty min after, the
speculum occluding the cannula is removed and 0.5 μl of saline (control rats) or saline containing different UFP-101 concentrations, are injected through a stainless-steel injector. Rat motor activity is then monitored in two following sessions carried out 10 and 60 min after injection, and quantified as percent of motor activity in the control session. As reported in Tab. 1, saline injection does not alter motor performance. On the contrary, UFP-101 injection produces a dose-dependent increase of performance, which is significant for the 1 and 10 nmol doses. At higher doses (30 nmol), UFP-101 also increases spontaneous locomotion, causing the animal to rotate in direction opposite to the injection side (i.e. contralaterally). This effect prevents the rat to remain on the cylinder. UFP-101 effect remains unchanged even after 60 min from injection. Effects of UFP-101 in the rat made cataleptic with haloperidol Seven days after surgery, rats are administered intraperitoneally (i.p.) with 0.8 mg/Kg haloperidol (dissolved in saline) and catalepsy measured by three different tests, already described in the literature: the bar test, the drag test and the swing test. Eighty min after haloperidol injection, the rat appears cataleptic and its movements dramatically reduced compared to a vehicle- treated control rat, as shown by the three tests (see Tab 2-4). Motor behaviour appears impaired also in a second test carried out 150 min after haloperidol injection. Seventy min after haloperidol injection the speculum is removed and saline (0.5 μl: control rats) or UFP-101 (30 nmol in 0.5 μl saline) is injected. UFP-101 effect appears dramatic when compared to saline-treated rats. Indeed, 10 min after administration, the contralateral paw as well as muscles contralateral to the injection side, appear released and motor performance almost normalized. Moreover, the rat shows increased spontaneous motor activity, since contralateral rotations appear. Beneficial effects of UFP-101 are
still observed eighty min after injection, at least in the bar and drag tests. Effects of UFP-lOlin the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rat This PD model is based on injection of 6-OHDA, a monoaminergic neuron toxin, in the DAergic ascending bundle, so to lesion DAergic neurons that project to the striatum and to reduce by more than 95 % DA levels in this nucleus. In detail, unilateral 6-OHDA lesion is made on male Sprague-
Dawley rats (150 g), the animals are anaesthetised with isoflurane and placed on a stereotaxic frame. A hole in parietal bone is then made and 4 μl of saline, containing 8 μg of 6-OHDA and 0.2 mg/ml of ascorbic acid are injected at
1 μl/min speed according to the following coordinates from bregma: AP= -4,4 mm; ML= -1.2 mm; ND= -7.8 mm. Sham-operated animals are injected with saline containing only ascorbic acid. Two weeks after surgery, degree of DA depletion is evaluated: a) by counting the number of ipsilateral rotations (i.e. rotations towards lesion side) induced by amphetamine (5 mg/kg; i.p.); b) by counting the time spent on the rod in the rotarod test. Approximately 5 weeks after lesion, the animals enrolled in the study
(i.e. those showing DA lesion of more than 95 %) are placed on a stereotaxic frame and implanted with an infusion cannula above the SΝr, following the procedures described above. After surgery, rats are trained to perform on the rotarod, and the experiment is carried out a week later. Saline or increasing
UFP-101 doses are thus injected in the SΝr. Saline does not significantly affect rat motor performance, while UFP-101 facilitates it, at doses at least 10 times lower than control rats (i.e. 0J e 1 nmol; Tab 5). Higher doses (10 e 30 nmol) produce increased spontaneous motor activity, inducing contralateral turning (Tab 6). Also in this case, the effect is evident at lower doses (10 nmol) and is more marked than in control rats.
Effects of levodopa in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rat The antiparkinsonian drug levodopa, administered systemically (i.p.;
300 μl) together with the DOPA-decarboxylase inhibitor benserazide (16 mg/Kg) , dose-dependently elevates rat performance in the rotarod test (Tab.
7). The effect is significant for the 0.3 mg/Kg and maximal for 6 mg/Kg dose. Effects of J-113397in the naϊve and 6-hydroxydopamine (6-OHDA) unilaterally lesioned rat The nonpeptide NOP receptor antagonist J-113397, administerd systemically (i.p.; 300 μl) dose-dependently elevates motor performance of both naϊve (Tab. 8) and hemiparkinsonian (Tab. 9) rats in the rotarod test. In hemiparkinsonian rats, however, the effect is significant at lower J-113397 doses (i.e. 0.1 mg/Kg). Maximal doses of J-113397 (1 mg/Kg) and levodopa (1 mg/Kg) combined and injected together (i.p. 300 μl) produce an additive facilitatory effect on the rotarod performance of hemiparkinsonian rats (Tab. 10). TABLES Tab 1. Rotarod test: effect of UFP-101 in naive rats. Effect of UFP-101 administration in the SNr on the rotarod performance in naive rats. Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after intranigral injection of UFP- 101. At high doses the animal cannot perform correctly the test since UFP-101 induces turning in direction opposite to the injection side (contralateral; CIV).
*P<0.05 different from saline
Tab. 2 Effect of UFP-101 on haloperidol-induced catalepsy: the bar test. Effect of SNr injection of 30 nmol UFP-101 on haloperidol-induced (0.8 mg/Kg; i.p.) catalepsy in naϊve rats, as measured by the bar test. This test measures the time spent by each forepaw on blocks of 3, 6 e 9 cm height. Data are expressed in arbitrary units (20 sec cut-off time) and represent mean ± SEM of at least 6 determinations, made 80 and 150 min after haloperidol injection. UFP-101 was administered 70 min after haloperidol injection. *P<0.05 different from haloperidol.
Tab. 3 Effect of UFP-101 on haloperidol-induced catalepsy: the drag test. Effect of SNr injection of 30 nmol UFP-101 on haloperidol-induced (0.8 mg/Kg; i.p.) catalepsy in naϊve rats, as measured by the drag test. This test measures the number of touches made by the rat with each forepaw in the attempt to maintain the correct posture while being dragged along a i m surface at 15 cm/sec speed. Data represent mean ± SEM of at least 6
determinations, made 80 and 150 min after haloperidol injection. UFP-101 was administered 70 min after haloperidol injection. *P<0.05 different from haloperidol.
Tab. 4. Effect of UFP-101 on haloperidol-induced catalepsy: the swing test. Effect of SNr injection of 30 nmol UFP-101 on haloperidol-induced (0.8 mg/Kg; i.p.) catalepsy in na'ϊve rats, as measured by the swing test. This test measures the number and direction of torsions made by the rat, after being raised from the tail (60 sec) along a vertical surface. Data represent mean ± SEM of at least 6 determinations, made 80 and 150 min after haloperidol injection. UFP-101 was administered 70 min after haloperidol injection. *P<0.05 different from haloperidol
Tab 5. Rotarod test: effect of di UFP-101 in hemiparkinsonian rats. Effect of UFP-101 administration in the SNr on motor performance of unilaterally 6-hydroxydopamine lesioned (hemiparkinsonian) rats in the rotarod test. Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after intranigral injection of UFP-101. At high doses the animal cannot perform correctly the
test since UFP-101 induces turning in direction opposite to the injection side (contralateral;C/L). *P<0.05 different from saline
Tab. 6. Contralateral rotations: effect of UFP-101 in naive and hemiparkinsonian rats. Effect of UFP-101 administration in the SNr on contralateral (i.e. in direction opposite to the injection side) rotations made by the rat within 20 min from injection. Data are mean ± SEM of at least 6 determinations. *P<0.05 different from saline
Tab 7. Rotarod test: effect of levodopa in hemiparkinsonian rats. Effect of levodopa administration on motor performance of unilaterally
6-hydroxydopamine lesioned (hemiparkinsonian) rats in the rotarod test. Levodopa has been administered i.p. in combination with benserazide (16 mg/Kg). Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after levodopa
administration. *P<0.05 different from saline
Effect of J-113397 administration on the rotarod performance in naive rats. Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after systemic (i.p.) injection of J- 113397. *P<0.05 different from saline
Tab 9. Rotarod test: effect of J-113397 in hemiparkinsonian rats. Effect of J-113397 administration on the rotarod performance in hemiparkinsonian rats. Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after systemic (i.p.) injection of J-113397.
*P<0.05 different from saline
Tab 10. Rotarod test: effect of levodopa plus J-113397 in hemiparkinsonian rats. Effect of simultaneous administration of levodopa and J-1 13397 on motor performance of unilaterally 6-hydroxydopamine lesioned (hemiparkinsonian) rats in the rotarod test. Levodopa (in combination with benserazide) and J-113397 were injected i.p. alone or in combination. Data are expressed as percent of control and represent means ± SEM of at least 6 determinations, made 10 and 60 min after levodopa administration. *P<0.05 different from saline P<0.05 different from J-113397 or levodopa alone
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