piperidines and prodipin

Patients with Parkinson's disease were treated with different antiparkinsonian drugs and the amino acid levels in serum and cerebrospinal fluid were determined. Results obtained in 43 patients (L-dopa [26]; prodipine [6]; amantadine [11]) are reported. All drugs investigated produced an increase in amino acids in serum and in CSF, this enhancement being most pronounced for neutral, long-chain amino acids. Amantadine, however, showed this effect for a short period, only. Our results lead us to assume that this increased pool of amino acids in the CSF facilities the biosynthesis of amines with transmitter function from their precursor amino acids.

Topics: Amantadine; Amino Acids; Antiparkinson Agents; Humans; Levodopa; Parkinson Disease; Piperidines

The influence of prodipin, a putative dopamine releasing compound, on the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the spinal liquor of 28 patients with Parkinson's disease was investigated. The patients were divided into three groups. In group 1 the combined antiparkinson therapy was interrupted, and 20 mg prodipin was infused. In group 2 and 3 the therapy was continued, while an additional 20 mg of prodipin was administered by infusion only to group 3. 4 Liquor-samples were obtained from each patient: 1 basic value and three additional samples 5, 8 and 24 hours after administration of 2 g probenecid. The base concentration of HVA was 15 ng/ml and this was not increased by probenecid in group 1; the concentration of 5-HIAA was 11.6 ng/ml and this was doubled by probenecid to 22.9 ng/ml. The HVA concentration increased to a maximum of 28.9 ng/ml during continued therapy (group 2); the elevated 5-HIAA remained unchanged. Prodipin does not cause an alteration in metabolite concentration in cases of interrupted therapy (group 1), but leads, in the case of continued therapy, to a 1.8-fold increase in HVA, and a 1.6-fold increase in 5-HIAA (group 3).

Topics: Aged; Antiparkinson Agents; Clinical Trials as Topic; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Parkinson Disease, Secondary; Phenylacetates; Piperidines; Time Factors

The CD26 antigen, one of the major costimulatory molecules in T cell activation, was shown to possess dipeptidyl peptidase IV (DPP IV) activity. Previously, we demonstrated that immunosuppressed kidney transplant patients exhibit lower DPP IV serum activity as compared with healthy individuals. In the present study, we analyzed the role of CD26/DPP IV in the immune cascade triggered by organ transplantation and leading to acute rejection of cardiac allografts in rat recipients. Transplantation of hearts from (Lewis x Brown Norway)F1 donors into Lewis hosts resulted in an early (24 hr) increase in cellular CD26 expression, followed by a rise in DPP IV serum activity, which peaked at day 6, i.e., before the time of actual graft loss. Specific targeting of DPP IV activity with a novel, low-molecular-weight inhibitor of the diphenyl-phosphonate group (prodipine) abrogated acute rejection and prolonged cardiac allograft survival to 14.0+/-0.9 days (P<0.0001). Prodipine treatment prevented the early peak of cellular CD26 expression and thoroughly suppressed systemic DPP IV activity. The inhibition of DPP IV was associated with severely impaired host cytotoxic T lymphocyte responses in vitro. These results demonstrate the role of CD26/DPP IV in alloantigen-mediated immune regulation in vivo and provide the first direct evidence that CD26/DPP IV plays an important role in the mechanism of allograft rejection. The model of targeting CD26/DPP IV may reveal essential interactions on the level of costimulatory alternate T cell activation pathways, allowing a more subtle approach for more selective immunosuppression in transplant recipients.

Topics: Animals; Dipeptidyl Peptidase 4; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Lymphocytes; Male; Piperidines; Protease Inhibitors; Rats; Rats, Inbred BN; Rats, Inbred Lew; T-Lymphocytes, Cytotoxic; Transplantation, Homologous

Dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5), also known as CD26, is a membrane-bound serine protease that cleaves off aminoterminal dipeptides from peptides with a penultimate proline (or, at a much slower rate, a penultimate alanine). Recently, we synthesized and characterized a number of dipeptide-derived diphenylphosphonates. Out of the resulting series of slow-binding irreversible inhibitors of DPP IV, diphenyl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate hydrochloride (Pro-Pro-diphenylphosphonate or Prodipine) was selected for further study. We investigated the in vivo applicability of Prodipine. Male rabbits weighing 3-4 kg received a single intravenous injection with 10 mg Prodipine or saline. After 1 hr, plasma DPP IV activity had decreased to less than 20% of the preinjection value and remained unchanged during a 24-hr observation period. In a next step, we aimed to study (i) the dose dependency and (ii) the duration of the effect after a single intravenous dose of Prodipine. A profound and long-lasting inhibition of plasma DPP IV activity was observed in the treated animals (1, 5 or 10 mg). It took 5 to 8 days to reach half of the pretreatment DPP IV activity and generally more than 20 days for a complete recovery. Systemic treatment with Prodipine not only led to inhibition of plasma DPP IV activity but also decreased tissue DPP IV activity in circulating mononuclear cells, kidney cortex, thymus, spleen, lung, and liver. No differences in activities of the related peptidases aminopeptidase P (APP, EC 3.4.11.9), prolyl oligopeptidase (PO, EC 3.4.21.26), or aminopeptidase M (mAAP, EC 3.4.11.2) were detected between Prodipine-treated and control rabbits. The in vivo applicability of this chemically stable, irreversible inhibitor of DPP IV opens new possibilities, not only to further unravel the biological functions of this intriguing ectopeptidase, but also to explore this enzyme as a new target in various fields of pharmacological research.

Topics: Aminopeptidases; Animals; Dipeptidyl Peptidase 4; Kidney Cortex; Liver; Lung; Male; Methionyl Aminopeptidases; Monocytes; Piperidines; Prolyl Oligopeptidases; Rabbits; Serine Endopeptidases; Spleen; Thymus Gland

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin which produces degeneration of the nigrostriatal bundles in the central nervous system of man and animals. In these areas of the brain are concentrated the receptor binding sites for [3H]MPTP. 1-Alkyl-4, 4-diphenylpiperidines displace [3H]MPTP from these binding sites with Ki values in the micromolar range. The t-butyl analogue in this class of substances, budipine, is a novel therapeutic agent for Parkinsonism whose mechanism has not yet been fully clarified. The affinity of budipine for the MPTP receptor binding site was determined as a Ki value of 2.2 microM. Other 4, 4-diphenylpiperidine derivatives such as 1-methyl-4, 4-diphenylpiperidine and 1-i-propyl-4, 4-diphenylpiperidine have substantially lower affinities. Monoamine oxidase inhibitors such as deprenyl, pargyline and harmaline have affinities to the MPTP receptors which parallel their affinity for the B type of monoamine oxidase (MAO B). This supports the theory that the MPTP receptor binding sites is identical with membrane bound MAO B.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Animals; Brain; Male; Neurotoxins; Piperidines; Pyridines; Pyridinium Compounds; Radioligand Assay; Rats; Rats, Inbred Lew; Receptors, Cholinergic; Synaptosomes

The in vitro uptake and release of 14C-5-hydroxy-tryptamine (14C-5-HT) by human blood platelets was examined, which were used in this study as a simple model for serotonergic nerve endings. Experimental conditions allowed measurement of initial velocity of uptake and excluded possible (re)uptake of recently liberated 14C-5-HT in the release studies. The effects of two new antiparkinson drugs, 1-isopropyl-4,4-diphenylpiperdine (prodipine) and its 1-tert-butyl analogue (budipine), on the two opposite transport processes of serotonin were investigated. Prodipine and budipine inhibit the uptake of 14C-5-HT by human blood platelets in a dose-dependent manner. Inhibition of uptake by both drugs is non-competitive; Ki values are 1.1X10(-4) mol/l for prodipine and 9X10(-5) mol/l for budipine, with prodipine additionally showing an effect on Km of serotonin for uptake system. Both substances liberate recently accumulated 14C-5-HT from the platelets. Stimulation of this process is dose-dependent, budipine proving more active than prodipine, both drugs being 5.4 and 4.1 times stronger than amantadine. The observed effects of prodipine and budipine on uptake and release of 14C-5-HT by isolated blood platelets are discussed in the light of other pharmacological activities and the antiparkinson efficacy of these drugs.

Topics: Adult; Antiparkinson Agents; Blood Platelets; Female; Humans; In Vitro Techniques; Kinetics; Male; Piperidines; Serotonin