dihydrexidine and Parkinson-Disease--Secondary

Previous studies have suggested a dopaminergic regulation of eye blink rates in human and nonhuman primates. Blockade of either dopamine (DA) D1 or DA D2 receptors or DA depletion induced by the dopaminergic neurotoxin MPTP both decrease spontaneous eye blink rates in monkeys. MPTP-induced decreases in blink rates can be reversed by administration of the full efficacy D1 agonist dihydrexidine, which has also been found to have dramatic antiparkinsonian effects in MPTP-treated animals. Increases in blink rates can also be induced by D1 and D2 agonists in normal animals. In the current study, we have investigated whether blink rates correlate with concentrations of DA or HVA and/or HVA:DA ratios in specific brain regions in MPTP-treated monkeys. Furthermore, the potential relationship between the severity of behavioral indices of parkinsonism and blink rates were examined. We found that (1) blink rates significantly correlate positively with concentration of DA and inversely with HVA:DA ratios in the rostral portion of the ventromedial body of the caudate nucleus (CD), but not other subcortical regions, and (2) that severity of parkinsonism was inversely correlated with blink rate. These data support a dopaminergic regulation of blink rate and suggest that the ventromedial region of the body of the CD may be critically involved in regulation of blink rate.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Blinking; Caudate Nucleus; Chlorocebus aethiops; Culture Techniques; Dopamine; Dopamine Agents; Dopamine Agonists; Homovanillic Acid; Male; Parkinson Disease, Secondary; Phenanthridines; Severity of Illness Index

A series of substituted 9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying with respect to the position of the thiophene relative to the benzo[f]quinoline core and the nature and position of the substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers bearing a small alky1 (C1-C3) substituent at the 2 position were potent (Ki < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds were resolved and found to exhibit a high level of enantiospecificity in their interaction with the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of Parkinson's disease and for their liability to produce seizure-like activities in mice. (5aR)-trans-2-Propyl-4,5,5a,6,7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (5) emerged as the compound with the best overall in vivo profile in terms of potency (ED50 = 0.04 mumol/kg) and safety.

Topics: Adenylyl Cyclases; Animals; Benzazepines; Binding, Competitive; Cell Membrane; Corpus Striatum; Dopamine Agonists; Dopamine Antagonists; Fishes; Mice; Molecular Structure; Oxidopamine; Parkinson Disease, Secondary; Quinolones; Receptors, Dopamine; Retina; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Tritium; Yohimbine

Dihydrexidine (trans-10,11-dihydroxy5,6,6a,7,8,12b hexanhyydrobenso- [alpha]phenanthridine) is a full dopamine D1 agonist. In rhesus macaque monkeys rendered hemiparkinsonian by unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dihydrexidine (0.15-0.9 mg/kg) elicited dose-dependent contralateral rotation. The effects of dihydrexidine were blocked by pretreatment with the D1 antagonist SCH 23390 (0.03 mg/kg), but not by the D2 antagonist raclopride (0.025 mg/kg). These results suggest a functional role for D1 receptors in stimulating motor behavior in a primate model of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Functional Laterality; Macaca mulatta; Male; Parkinson Disease, Secondary; Phenanthridines; Quinpirole; Raclopride; Receptors, Dopamine D1; Rotation; Salicylamides

Monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over long periods of time develop cognitive deficits without severe parkinsonian motor signs. In the present study we assessed the effects of the selective and full dopamine D-1 receptor agonist dihydrexidine on delayed response deficits in chronic low dose (CLD) MPTP-treated monkeys. Dihydrexidine caused a dose-dependent improvement in task performance, that could be blocked by the D-1 receptor antagonist SCH-23390. In addition to reducing the number of mistakes made during delayed response performance, dihydrexidine also improved task persistence. These data suggest that dihydrexidine may be useful in treating cognitive as well as motor deficits of parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzazepines; Dopamine Agonists; Dose-Response Relationship, Drug; Female; Macaca fascicularis; Macaca nemestrina; Male; Parkinson Disease, Secondary; Phenanthridines; Psychomotor Performance; Random Allocation; Receptors, Dopamine D1

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Chlorocebus aethiops; Dopamine; Dopamine Agents; Male; Parkinson Disease, Secondary; Phenanthridines