A review of the receptor-binding and pharmacokinetic properties of dopamine agonists.

BACKGROUND: Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease. OBJECTIVES: This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events. METHODS: Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole. RESULTS: Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D(1) receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT(2B) (and possibly 5-HT(2A)) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls. CONCLUSIONS: As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D(1) receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system.

Phosphoproteome and transcriptome analysis of the neuronal response to a CDK5 inhibitor.

In Alzheimer's disease and amyotrophic lateral sclerosis deregulation of cyclin-dependent kinase 5 (CDK5) causes hyperphosphorylation of tau and neurofilament proteins, respectively, leading to neuronal cell death. We have demonstrated recently that pharmacological inhibition of CDK5 protects neurons under various stressful conditions (Weishaupt J. H., et al., Molec. Cell. Neurosci. 2003, 24, 489-502). To get an overview on the cellular mechanisms of action we analyzed global changes in protein phosphorylation in cultured cerebellar granule neurons by [(32)P]orthophosphate labeling after administration of a CDK5 inhibitor. Since CDK5 has recently been shown to phosphorylate and inactivate transcription factor MEF2, we included gene expression profiling using cDNA microarrays. By two-dimensional gel electrophoresis and matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry we identified several phosphoproteins that were modulated by compound administration. Among them syndapin I which is involved in vesicle recycling, and dynein light intermediate chain 2 which represents a regulatory subunit of the dynein protein complex. These findings are consistent with the known physiological function of CDK5 in synaptic signaling and axonal transport. Moreover, we detected phosphoproteins acting in neuronal surival and/or neurite outgrowth, such as cofilin and collapsin response mediator protein. Subsequent testing in cell cultures revealed that the CDK5 inhibitor blocked mitochondrial translocation of pro-apoptotic cofilin in cerebellar granule neurons and enhanced neurite outgrowth in dorsal root ganglia. Numerous genes exhibiting MEF2 consensus binding sequences were modulated by CDK5 inhibitor treatment. Among them some that may contribute to neurite elongation or neuronal survival, but also several genes functioning in synaptic transmission. Taken together, phosphoproteome and transcriptome analysis indicate that the compound promotes both neuronal survival and neurite outgrowth, but also may affect synaptic function in cultured neurons.

Differential effects of immunophilin-ligands (FK506 and V-10,367) on survival and regeneration of rat retinal ganglion cells in vitro and after optic nerve crush in vivo.

Immunophilins belong to the large family of peptidyl-prolyl-cis-trans-isomerases known to be involved in many cellular processes (e.g., protein trafficking and transcriptional regulation). Beside the widespread therapeutic use of ligands of immunophilins as immunosuppressants, it has been shown that some of these compounds such as FK506 and V-10,367 may mediate neuroprotection and improve axonal regeneration following damage to peripheral nerve fibers. Here, we have analyzed the effects of these two compounds on neurite outgrowth of retinal explants in vitro and on axonal regeneration of retinal ganglion cells, a population of central intrinsic neurons, ten days following optic nerve crush in vivo. FK506 enhanced neurite outgrowth/regrowth in vitro in a dose dependent manner up to 135% (control = 100%), while V-10,367 was more effective (up to 168%). In vivo, intravitreal V-10,367 and FK506 significantly reduced the number of dying retinal ganglion cells as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Local application of FK506 into the vitreous body, but not V-10,367, immediately provided after the optic nerve crush induced the elongation of regenerating fibers across the lesion site for around 1.2 mm. Our data provide evidence that the ligands of the FK506-binding proteins FK506 and V-10,367 protect (otherwise dying) retinal ganglion cells from optic nerve crush-induced cell death, promote neurite outgrowth in vitro and that locally applied FK506 enhances the sprouting of axotomized central intrinsic neurons such as retinal ganglion cells in vivo after optic nerve crush.

Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects.

Sabiporide, a new benzoguanidine, was characterized on fibroblasts stably expressing the Na(+)/H(+) exchanger isoforms NHE-1, NHE-2 and NHE-3. 22Na(+) uptake experiments show that this compound possesses a K(i) of 5+/-1.2 x 10(-8) M for NHE-1, and discriminates efficiently between the NHE-1, -2 and -3 isoforms (K(i) for NHE-2: 3+/-0.9 x 10(-6) M, and K(i)>1 mM for NHE-3). Similar K(i) values are obtained on rat cardiomyocytes and human platelets expressing NHE-1 (K(i)'s of 7+/-1 x 10(-9) and 2.7+/-0.4 x 10(-8) M respectively). Interestingly, when compared with amiloride and cariporide, sabiporide inhibition persists even after this molecule had been rinsed out (half time of 7 h for sabiporide, and of 1 and 2.5 min for amiloride and cariporide, respectively), the decay of all these molecules exhibiting a complex multiexponential behavior. Thus, sabiporide, which possesses remarkable cardioprotective properties, is a specific NHE-1 inhibitor possessing unique binding kinetics.