Disease relevance of N-0924

• Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease [1].
• (+)N-0437 (25-50 mumol/kg) was active in the first three models, but did not cause catalepsy [2].
• Moreover, transdermal dopaminergic drugs, particularly rotigotine, seem the ideal treatment for patients experiencing restless legs syndrome or periodic limb movement disorder during sleep, disorders that are quite common in elderly people or in association with neurodegenerative diseases [3].

Psychiatry related information on N-0924

• After repeated administration at doses of 0.05, 0.5, 1, and 5 mg/kg, rotigotine increased spontaneous motor activity at the 5 mg/kg dose after 3-5 days of treatment [4].
• Rotigotine (0.5, 1, and 5 mg/kg/day for 5 days) reversed the active avoidance deficit of helpless rats in the learned helplessness test, as shown by a significant decrease in escape failures after 3 to 4 days (0.5 mg/kg/day), 5 days (1 mg/kg/day), and 3 to 5 days (5 mg/kg/day) of treatment [4].
• In this study (+)N-0437 was investigated for its antagonistic activity at postsynaptic DA receptors in four behavioural tests which are commonly used to evaluate potential neuroleptic activity, i.e. d-amphetamine-induced stereotypy, passive avoidance responding, intracranial self-stimulation behaviour, and catalepsy [2].
• Reinforcement delays exceeding 200 ms largely eliminated the reinforcing efficacy of the D2 agonist N-0437 in CA1 operant conditioning [5].

High impact information on N-0924

• At the D2 receptors in the mouse vas deferens (alpha-2 blocked) the potency order was (+)-propyl-9-hydroxy-naphtoxazine > pergolide > N-0923 = apomorphine > bromocriptine > quinpirole > dopamine [6].
• N-0923 was therefore the most D2 receptor selective agonist tested.(ABSTRACT TRUNCATED AT 250 WORDS)[6]
• Experiments were carried out using the D2 dopamine receptor-selective agonist (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923) in the rat and the mouse isolated vas deferens to determine whether these tissues contained inhibitory D2 receptors in addition to their inhibitory alpha-2 adrenoceptors [6].
• Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1) [7].
• The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356 [8].

Chemical compound and disease context of N-0924

• For example, transdermal lisuride and apomorphine have been shown to reduce motor fluctuations and duration of 'off' periods in advanced Parkinson's disease, while rotigotine allows significant down-titration of levodopa without severe adverse effects [3].
• Rotigotine, an investigational dopamine agonist formulated as a patch, is being studied in Parkinson's disease [9].

Biological context of N-0924

• N-0437 (1.0 and 3.0 mg/kg) significantly reduced food intake, but had no effect on the duration of feeding, the duration and frequency of feeding bouts, or on the time course of feeding [10].
• In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i.e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-amino-phenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues [11].
• In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured [12].
• In contrast the isobutyryl ester, a prodrug with a relatively rapid hydrolysis rate, gave an improvement of turning behaviour over the whole time course in comparison with N-0437 [13].
• Furthermore, N-0437 inhibited the calcium-dependent release of [3H]dopamine (IC50: 4 nM) and [3H]acetylcholine (IC50: 6.3 nM) from rabbit striatal slices in the nanomolar range [14].

Anatomical context of N-0924

• Prejunctional adrenoceptor activity of N-0437, 2[N-n-propyl-N-2-(thienylethyl-amino)-5-hydroxytetralin], was investigated by means of the cat nictitating membrane (CNM) preparation [15].
• N-0923, [-]2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin HCl, recognizes the high and low affinity states of the D2 receptor in membranes from bovine caudate with a Klow of 79 nM [16].
• Intra-arterial (i.a.) administration of N-0437 produced a dose-related inhibition (ED50 = 14 micrograms) of the CNM contractions elicited by electrical stimulation of pre- and postganglionic sympathetic nerves of the superior cervical ganglion [15].
• In this article we quantified the isotopic separation by reversed-phase HPLC of the unlabeled N-0437, its deuterated and tritiated analogs, and their corresponding glucuronides, synthesized in vitro by rat liver microsomes [17].

Associations of N-0924 with other chemical compounds

• In the mouse vas deferens N-0923 and the alpha-2 adrenoceptor agonist clonidine inhibited the electrically evoked twitch responses [6].
• In an attempt to improve the bioavailability, eight ester prodrugs of N-0437 were synthesized, i.e. the acetyl, isobutyryl, pivaloyl, benzoyl, 2-methylbenzoyl, 2-methoxybenzoyl, 2,4-dimethylbenzoyl and 2-aminobenzoyl analogues [13].
• Hydroxylation of N-0437 at the position ortho to the phenolic group present yielded a catechol intermediate, which was excreted as a glucuronide and accounted for about 10% of the dose [18].
• A series of new dopamine (DA) receptor agonists, of the 2-aminotetralin group, i.e. N-0434, N-0437 and N-0734 were investigated in both in vivo and in vitro pharmacological test systems [19].
• Nevertheless, significant, dose-dependent reductions in sucrose consumption were observed after the administration of either opiate antagonists (naltrexone; nalmefene) or selective dopamine D2 receptor agonists (N-0437; quinpirole) [20].

Gene context of N-0924

• N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson's disease [16].
• 4. N-0923 also inhibits dopamine uptake and prolactin secretion, and it is an antagonist at the alpha 2 receptor [16].
• A pharmacokinetic study of the dopamine D2 receptor agonist (S)-(-)-2-(N-propyl-N-(2-thienylethyl)amino)-5-hydroxytetralin+ ++-HCl (N-0923) infused in female cynomolgus monkeys over a 4-h period was carried out at International Research and Development Corporation [21].
• Dopamine (500 nM) or the dopamine agonists lisuride (50 nM), terguride (50 nM), and N-0437 (50 nM) decreased maitotoxin-stimulated prolactin release from perifused MMQ cells [22].
• Substitution of a propyl side chain by a thienylethyl-, or phenylethyl side chain, in 5-hydroxy-DPAT, or in (+)-4-propyl-9-hydroxyhexahydronaphthoxazine (PHNO, N-0500), showed a large increase of the UDPGT affinity and intrinsic clearance especially for N-0437 [23].

Analytical, diagnostic and therapeutic context of N-0924

• The maximum Flux(ss) achieved was around 80 nmol cm(-2) h(-1) indicating that by means of iontophoresis, a therapeutic level of rotigotine might be achieved with a reasonable patch size [24].
• Isotopic separations of the drug N-0437 and its diastereoisomeric glucuronides by high-performance liquid chromatography [17].
• In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway [11].
• The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group [11].
• Microdialysis and striatal dopamine release: stereoselective actions of the enantiomers of N-0437 [25].

References