In-vitro and in-vivo metabolism of the presynaptic dopamine agonist 3-PPP to a catecholic analogue in rats

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 microM and 2 nmol (mg protein)-1 min-1 respectively. As the catecholamine formed appears to be a good substrate for catechol-O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g-1 after i.p., and about 100 pmol g-1 after s.c. injection of 45 mumol kg-1 3-PPP, with no significant difference between racemic, ( + ) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1-5% of the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed

Transdermal administration of the dopamine agonist N-0437 and seven ester prodrugs: comparison with oral administration in the 6-OHDA turning model

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. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were sythesized, i.e the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-aminophenyl 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues. 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, From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl- and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application

Effect of the α4β2∗ nicotinic acetylcholine receptor partial agonist varenicline on dopamine release in β2 knock-out mice with selective re-expression of the β2 subunit in the ventral tegmental area

International audienceWe studied the effects of 1 mg/kg doses of nicotine and the alpha4beta2* nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, on extracellular dopamine (DA) levels in the nucleus accumbens (NuAcc) of lentivirally vectorized male mice. Three separate experimental groups were injected with a lentiviral vector transducing the ventral tegmental area (VTA): wild-type C57BL/6J mice with a vector expressing eGFP only, beta2 knock-out mice (beta2KO) with the eGFP-only vector, and beta2KO mice with a bicistronic vector reintroducing beta2 and eGFP into the VTA as recently described (Maskos et al., 2005). Our results suggest that the neurochemical effects of varenicline as measured by using microdialysis in awake, freely moving mice are mainly mediated via beta2* nAChR subunits localized in the VTA

Orally Active Carbamate Prodrugs of the Selective Dopamine Agonist N‐0437: In‐vivo Activities in the 6‐OHDA Turning Model and In‐vitro Activities

The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37-degrees-C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors

HPLC-assay with electrochemical detection for the neurotoxin MPTP, its metabolite MPP+ and MPTP-analogues in biological samples after purification over sephadex G10

A sensitive and selective method for assaying the neurotoxin MPTP and some MPTP-analogues in mouse brain and serum is described. The method is based on isolation of the compounds from biological samples on small Sephadex G10 columns followed by reverse phase HPLC with amperometric detection. HPLC separation was performed at pH 3, after which the the pH was increased to 6.8 by mixing the column effluent with 0.5 M phosphate pH 9, to provide the conditions required for electrochemical detection. A metabolite of MPTP, MPP+, was determined as MPTP after reduction with NaBH4. This assay allows the determination of brain and serum concentrations in the pmol/g range of administered MPTP and MPTP-analogues and the effects of these substances on dopamine and its metabolites in the same tissue sample

ABBREVIATIONS: MPTP, 1-methyl-4-phenyl MPP -Iike Neurotoxicity of a Pyridinium Metabolite Derived from Haloperidol: In Vivo Microdialysis and In Vitro Mitochondrial Studies1

ABSTRACT Intracerebral (intrastriatal, intranigral and intracortical

Brain and serum concentrations of dopamine analogues after peripheral administration to rats

Concentrations of dopamine (DA) analogues were determined in rat brain regions and serum after peripheral administration of the drugs. The time course of the concentrations of four N,N-dialkylated DA derivatives is reported in relation to the simultaneously measured effects on DA metabolism. Maximum brain concentrations were reached at about 10 min after injection, followed by a rapid elimination of the parent compounds. O-Methylation was found to be of major importance in this early disappearance. The 3-O-methyl metabolite of N,N-dipropyl-DA (DiPr-DA) was very rapidly formed and was eliminated much more slowly than the parent compound. Inhibition of O-methylation as well as subcutaneous, instead of intraperitoneal (ip), administration resulted in higher brain and serum levels of DiPr-DA. Brain concentrations of 11 DA analogues were determined 10 min after ip injection and were compared with their octanol/water (pH 7.4) partition coefficients. Within one group of compounds with a similar metabolic profile the brain concentrations and partition coefficients showed a good correlation

Coil-helix transition of ι-carrageenan as a function of chain regularity

A series of ι-carrageenans containing different amounts of v-carrageenan (0-23 monomer %) have been prepared from neutrally extracted carrageenan of Eucheuma denticulatum. v-Carrageenan is the biochemical precursor of ι-carrageenan. The conformational order-disorder transition and rheological properties of these carrageenans were studied using optical rotation, rheometry, size exclusion chromatography coupled to multiangle laser light scattering, and high-sensitivity differential scanning calorimetry. The helix forming capacity of ι-carrageenan turns out to decrease monotonously with increasing amount of v-units. In contrast, the rheological properties of ι-carrageenan are remarkably enhanced by the presence of a small amount of v-units, yielding a maximum twofold increase in G′ at 3% v-units. It is concluded that the structure-forming capacity of ι-carrageenan, containing a small amount of v-carrageenan, is significantly higher than that of pure ι-carrageenan. This phenomenon is explained in terms of the balance between the helical content and the number of cross-links between chains, taking into consideration the fact that v-units introduce "kinks" in the chain conformation enabling neighboring chains to connect. Increasing amounts of v-units increase the number of cross-links in the network, resulting in increased gel strength. On the other hand, a reduced length of the helical strands weakens the cross-links between the different chains and, consequently, the gel. © 2002 Wiley Periodicals, Inc. Chemicals/CAS: Carrageenan, 9000-07-1; Gel