ABSTRACT
Studies described here tested the hypothesis that phosphodiesterase 10A inhibition by a selective antagonist, MP-10, activates the dopamine D2 receptor expressing medium spiny neurons to a greater extent than the D1 receptor expressing neurons. We used regional pattern of c-Fos induction in the neostriatal subregions of rodents and direct assessment of D1-positive and -negative neurons in the DRd1a-tdTomato mice for the purpose. MP-10 (1, 3, 10 or 30 mg/kg, PO) dose-dependently increased c-Fos immunopositive nuclei in all regions of neostriatum. However, the effect was statistically greater in the dorsolateral striatum, a region known to be activated preferentially by the D2 antagonism, than the D1-activated dorsomedial striatum. The D2 antagonist, haloperidol (0.3, 1, or 3 mg/kg, PO) produced an identical, regional pattern of c-Fos induction favoring the dorsolateral striatum of the rat. In contrast, the D1 agonist, SKF82958 (0.5, 1, or 2 mg/kg, PO), induced greater expression of c-Fos in the dorsomedial striatum. The C57Bl/6 mouse also showed regionally preferential c-Fos activation by haloperidol (2 mg/kg, IP) and SKF82858 (3 mg/kg, IP). In the Drd1a-tdTomato mice, MP-10 (3 or 10 mg/kg, IP) increased c-Fos immunoreactivity in both types of neurons, the induction was greater in the D1-negative neurons. Taken together, both the regional pattern of c-Fos induction in the striatal sub-regions and the greater induction of c-Fos in the D1-negative neurons indicate that PDE10A inhibition produces a small but significantly greater activation of the D2-containing striatopallidal pathway.
Subject(s)
Neostriatum/drug effects , Neurons/drug effects , Phosphodiesterase Inhibitors/pharmacology , Pyrazoles/pharmacology , Quinolines/pharmacology , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Animals , Benzazepines/pharmacology , Dopamine Agonists/pharmacology , Dopamine D2 Receptor Antagonists/pharmacology , Dose-Response Relationship, Drug , Haloperidol/pharmacology , Male , Mice, Inbred C57BL , Mice, Transgenic , Neostriatum/metabolism , Neostriatum/pathology , Neurons/metabolism , Neurons/pathology , Phosphoric Diester Hydrolases/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Random Allocation , Rats, Sprague-Dawley , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D1/geneticsABSTRACT
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Haplorhini , Isoquinolines/chemistry , Molecular Sequence Data , Prodrugs/chemistry , Receptors, Kainic Acid/chemistry , Structure-Activity RelationshipABSTRACT
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Tetrazoles/pharmacology , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Isoquinolines/chemistry , Male , Molecular Sequence Data , Prodrugs/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Subject(s)
Amino Acids/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Pain/drug therapy , Receptors, Kainic Acid/antagonists & inhibitors , Analgesics/pharmacokinetics , Animals , Biological Availability , Cell Line , Disease Models, Animal , Humans , Hyperalgesia/drug therapy , Rats , Receptors, AMPA/metabolism , Recombinant Proteins/metabolism , Spinal Cord/physiopathology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolismABSTRACT
Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.
