Shunji Ichikawa

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

Abstract Rationale: Current treatment of Parkinson’s disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. Objectives: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro-1H-purine-2,6-dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson’s disease. Methods: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. Results: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and l-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. Conclusions: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson’s disease, and may offer a new therapeutic approach to the treatment of Parkinson’s disease.

Stimulating action of KW-5139 (Leu13-motilin) on gastrointestinal motility in the rabbit

1 The gastrointestinal motor stimulating action of the motilin analogue, KW‐5139 (Leu13‐motilin), was investigated both in the anaesthetized rabbit and in rabbit isolated smooth muscle tissues. 2 KW‐5139 (0.3–10 μg kg−1, i.v.) produced motor stimulating actions in the gastric antrum, ileum and descending colon, the excitatory responses of which were initiated at the same time but declined with different time courses. The rank order of the excitatory response was: descending colon ≥ gastric antrum >> ileum. 3 Atropine (1–3 mg kg−1, i.v.) or naloxone (1 mg kg−1, i.v.) completely suppressed the excitatory response to KW‐5139 in the gastric antrum, but only partially attenuated that in the descending colon. This suggests that the mechanism of the excitatory response is different in the gastric antrum and the descending colon, and that cholinergic neural pathway is involved in the response of the gastric antrum. 4 KW‐5139 (0.1 nM‐1 μm) caused concentration‐dependent contractions of the gastric antrum, duodenum, jejunum, ileum and the descending colon in vitro. In the rabbit intestine, the contractile response to KW‐5139 was strongest in the duodenum and weakest in the ileum. 5 The contractile response to KW‐5139 in the intestinal segments were not affected by tetrodotoxin, but were decreased by verapamil, or pretreatment with a high concentration of porcine motilin, confirming the involvement of motilin receptors in the response to KW‐5139. 6 The present results suggest that the rabbit is a suitable species for the investigation of motilin on gut motility, because of the high responsiveness of the descending colon as well as the upper gastrointestinal tract.

Synthesis and in vitro gastrointestinal motility enhancing activity of 3-aryl-2-imidazolidinylidene propanedinitrile derivatives

Abstract Novel N -3-arylated imidazolidinylidene propanedinitrile derivatives 2a–f were prepared by a new intramolecular cyclization method and their AChE inhibitory activity and in vitro gastrointestinal motility enhancing activity were evaluated. All compounds except 2f were found to be potent in both activities.