CY 208-243 behaves as a typical D-1 agonist in the reserpine-treated mouse.
The object of this study was to determine if the newly developed phenanthridine derivative, CY 208-243, retains its apparent in vivo preference for dopamine D-1 receptors under conditions of dopamine depletion, as a starting point to understanding why CY 208-243 possesses antiparkinson activity and the selective D-1 agonist SKF 38393 does not. Three hours after receiving reserpine (5 mg/kg), mice were strongly sedated and completely unresponsive to the motor stimulant effects of CY 208-243 (0.1-10 mg/kg) or the selective D-2 agonist RU 24213 (0.5-5 mg/kg) administered alone. After 24 h reserpine, the akinesia was partially and dose-dependent reversed by both CY 208-243 (0.1-10 mg/kg) and RU 24213 (0.5-5 mg/kg) alone. CY 208-243 also stimulated rearing and grooming, while RU 24213 gave rise to strong head-down sniffing. The response to 1 mg/kg CY 208-243 was practically abolished by pretreatment with the D-1 antagonist SCH 23390 (0.2 mg/kg). On the other hand, blocking D-2 receptors with metoclopramide (0.25 mg/kg) unexpectedly facilitated CY 208-243-induced locomotion and rearing, but suppressed grooming. When CY 208-243 (1 mg/kg) was injected together with RU 24213 (0.5-5 mg/kg), the two drugs interacted synergistically to stimulate locomotion at all times after reserpine. These animals also exhibited a greater preponderance of grooming, sniffing, gnawing and oral dyskinesia. Apart from the potentiation of some elements of CY 208-243-stimulated motor behaviour by D-2 blockade, these results are qualitatively indistinguishable from those previously obtained with the prototype D-1 agonist SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)
Abbott
B
B
Department of Pharmacology, School of Pharmacy, London, UK.
Starr
B S
BS
Starr
M S
MS
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006120:Grooming / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010617:Phenanthridines / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D011930:Reaction Time; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D012110:Reserpine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001552:Benzazepines; D015259:Dopamine Agents; D007211:Indoles; D010617:Phenanthridines; D010627:Phenethylamines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C054531:CY 208-243; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C016868:N-n-propyl-N-phenylethyl-4(3-hydroxyphenyl)ethylamine hydrochloride; D012110:Reserpine; D008787:Metoclopramide