zyxwvutsrqp zyxwvutsrqpo zyxwvutsrqponml zyxwvutsr Mowmenr Disorders Vol. 4. No. 3, 1989. pp. 7-61-265 0 1989 Movement Disorder Society Antiparkinsonian Activity of CY 208-243, a Partial D-1 Dopamine Receptor Agonist, in MPTP-Treated Marmosets and Patients with Parkinson’s Disease zyxwv zyxw J. A. Temlett, *N.P. Quinn, P. G. Jenner, *C. D. Marsden, tE. Pourcher, tA.-M. Bonnet, t Y . Agid, SR. Markstein, and SX. Lataste Universio Department of Neurology, Institute of Psychiatry and King’s College School of Medicine and Dentistry, *The Institute of Neurology, Queen Square, London, England; tClinique de Neurologie et Neuropsychologie, INSERM U-289, Hopital de la Salpetriere, Paris, France; and $Sandoz Ltd, B a d e , Switzerland. Summary: The effect of stimulation of cerebral dopamine D-1 receptors by CY 208-243 on motor disability was tested in MPTP-treated parkinsonian marmosets and patients with Parkinson’s disease. CY 208-243 (0.5-1.25 mg/kg s.c.) produced a dose-related reversal of akinesia and rigidity in the marmosets, lasting some 2 h. Single morning doses of CY 208-243 (5-40 mg) were compared with the usual morning dose of levodopa in eight patients with Parkinson’s disease on long-term levodopa therapy who had developed motor fluctuations from immobility with akinesia and rigidity (off) to mobility often with dyskinesias (on). CY 208-243 alone was capable of switching such patients from off to on; five of the eight patients responded to the highest dose (40 mg), sometimes with dyskinesias. The response to CY 208-243 was comparable to that produced by levodopa in these cases. Drugs designed to stimulate both dopamine D, and D, receptors in the brain may improve the therapy of Parkinson’s disease. Key Words: Parkinson’s Disease-D-1 Agonist Drugs-CY 208-243. Large numbers of both dopamine D, and D, receptors are present in human striatum. Hitherto, all dopamine-active drugs used in the treatment of Parkinson’s disease have possessed D, agonist activity (11, but only some have exhibited additional D, receptor agonism. As a result, the role of D, receptor stimulation in the treatment of this disease is unknown. CY 208-243, (-)-(6aR) (12bR)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]-phenanthridine (Sandoz, Address correspondence and reprint requests to Dr. C. D. Marsden at the Institute of Neurology, Queen Square, London WClN 3BG, England. 26 I z 262 zyxwvutsrq zyxwvut zyxw J . A . TEMLETT ET A L . Bade), is a new selective dopamine D, receptor partial agonist. In vitro, it stimulates adenylate cyclase in rat striatum and bovine retina (D, effect) and fails to inhibit electrically evoked acetylcholine release in striatal slices (D, effect) (2). Nor does it produce D, action in vivo in animals. Thus, it does not cause emesis in dogs, lower prolactin in rats and humans, or increase tyrosine hydroxylase activity and dopamine turnover in rat striatum. Studies of circling behavior in unilaterally 6-OH-dopamine-lesioned rats indicate motor stimulant effects, which can be blocked by the selective D, antagonist SCH 23390, but not by the selective D, antagonist sulpiride (3). We, therefore, have investigated the antiparkinsonian activity of CY 208-243 in MPTP-treated parkinsonian marmosets and in patients with Parkinson’s disease. STUDIES IN MPTP TREATED MARMOSETS zy zy Adult common marmosets were given MPTP 2 mglkg s.c., daily for 5 days, to a cumulative dose of 10 mg/kg. After this treatment, all animals developed persistent motor deficits comprising marked bradykinesia, flexed posture, rigidity, and intermittent rest tremor. After 9 weeks, the animals had improved sufficiently from the acute effects to feed and groom themselves, but remained stable and grossly parkinsonian over the following 6 months. Individual animals were placed in a new cage, identical to their usual one, but fitted with seven infrared photocells. Three were focused horizontally across the width of the cage floor and one along the width of each of two perches. One beam was directed from front to back of the cage above each perch. This arrangement allowed assessment of movement in all directions. An acclimatization period of 30 min was allowed prior to drug treatment. Movement counts were accumulated over 10-min periods for at least 180 min following drug administration. Cumulative counts over a given period could be subanalyzed to show whether the animal spent time on the perches or on the cage floor. CY 208-243 was mixed with an equal weight of tartaric acid and dissolved in 0.9% sterile saline, and then the pH was adjusted with 0.1 M NaOH to 5.5. After a drug-free period of 2 weeks, control vehicle injections or CY 208-243 (0.5, 1.0, and 1.25 mdkg s.c.) were administered in a random dose sequence following a 30-min acclimatization period in the photocell cages. Thereafter, activity was monitored over a 3-h period. Animals were given 48-72 h to recover between doses. Student’s t test for paired samples was employed to assess differences between different drug treatments. Prior to drug administration, all the MPTP-treated marmosets had markedly decreased motility, spending most of the time on the floor of the cage or in one place on the lower of the two perches, and remained akinetic and flexed. Administration of the vehicle alone had no effect on motor activity. Administration of CY 208-243 produced a dose-related reversal of the motor deficits within a few minutes of drug administration, which reached a peak within 30 min (Fig. I). The reversal of motor deficits and the accompanying locomotor hyperactivity lasted for -2 h. Higher doses of CY 208-243 were not used in these studies since preliminary investigations showed these to induce hyperexcitability . zyx Movement Disorders, Vol. 4, N o . 3, 1989 zyxwv zyxw zy ANTIPARKINSONIAN ACTIVITY OF CY 208-243 263 zyxwvutsrqp zyxwvut zyxwvu zyxwvuts i1 FIG. 1. The effect of CY 208-243 (0.5-1.25 mg/ kg s.c.) compared with vehicle (V) on locomotor activity in MPTP-treated marmosets. The values shown are the means ( 2 1 SE) for eight individual animals. Movement counts were accumulated over 10-min periods for 3 h. *p < 0.05 or greater, Student's r test for paired samples. 1.0 125 zyxwvuts CLINICAL STUDIES The effects of CY 208-243 were investigated in eight inpatients with idiopathic Parkinson's disease (seven men and one woman, aged 50-73 years, with a median of 61 years), who gave informed consent to enter the study, which was approved by the Hospital Ethical Committee. They were at Hoehn and Yahr stage 111o r IV off medication, and had the disease for 9-18 (median of 12) years. All were experiencing motor fluctuations in response to long-term levodopa therapy (dose range of 400-2,400 mg/day, median of 800 mg/day, plus a peripheral decarboxylase inhibitor), which was withdrawn overnight before each study day. Other drugs were continued unchanged. CY 208-243 was given in open fashion by mouth on alternate mornings after breakfast in single doses of 5 (n = 5 ) , 10 (n = 7), 20 (n = 8), and 40 (n = 7) mg, respectively (Table 1). Blood pressure and pulse, and a score of motor disability [section 3 of the Unified Parkinson's Scale (4)] were measured at time 0, halfhourly for the first 2 h, and then hourly for the next 4 h. If no clinical benefit was apparent after 3 h or if any improvement lasted less than 3 h, the patient was given their usual morning dose of levodopa. The response of each patient to their usual dose of levodopa also was assessed on one occasion in one patient, twice in four patients, and three times or more in the remaining three patients. zyxwvu TABLE 1. The number of patients turning on, or partially on, after each dose of C Y 208-243 Dose of CY 208-243 (mgf n On 112 On Off 5 10 5 7 8 7 0 0 1 1 2 4 0 1 5 5 6 2 20 40 Movernenf Disorders. Vol. 4 , N o . 3, 1989 264 zyxw zyxwvuts zyxwv zyxw J . A . TEMLETT ET A L . Figure 2 shows the clinical response, judged by motor disability scores, of the patients to each dose of CY 208-243 and their usual response to levodopa. All eight patients turned on in response to their usual morning dose of levodopa; they rapidly switched from severe akinesia and rigidity (off) to near normal mobility, often with dyskinesias (on). With doses of CY 208-243 <40 mg, only occasional improvement was noted. After 10 mg, one patient turned fully on and another partially on (although he subsequently failed t o turn on after 20 and 40 mg). After 20 mg, two patients turned on. However, with 40 mg, four of seven patients turned o n and one partially on. The full on response with 40 mg occurred after 30-90 (median of 42.5) min and lasted 30-150 (median of 85) min; the patients turned off again 75-180 (median of 150) min after drug ingestion. Mild dyskinesias in two patients who turned fully on, nausea in two subjects, and drowsiness in one were encountered. N o postural hypotension, confusion or vomiting was noted, and no significant laboratory electrocardiogram (ECG) abnormalities were found. DISCUSSION The studies in the MPTP-treated marmoset showed CY 208-243 to reverse akinesia in this animal model of Parkinson’s disease in dose-related fashion. This confirms similar observations in squirrel monkeys (R. Markstein, unpublished observations). In the clinical study of CY 208-243, the drug clearly produced an on response comparable to that achieved with levodopa in four of eight patients. Of the four patients who turned on following the 40 mg dose of CY 208-243, two had dyskinesias similar to those produced by levodopa. Previous studies with another putative partial D, agonist SKF 38393 showed no effect of the drug on either parkinsonian motor signs in marmosets (5,6) or humans (7), or on levodopainduced dyskinesias in patients with Parkinson’s disease (7). The failure of S K F 38393 to affect parkinsonian marmosets or patients with Parkinson’s disease might be due to relatively poor penetration into brain or weak cerebral D, agonist 6o FIG. 2. Motor disability scores (on part 3 of the Unified Parkinson’s Scaie-ordinate) in eight patients off therapy (baseline) prior to drug administration (left hand column; B), at the time of maximum response to their usual morning dose of levodopa (100-225 mg with a peripheral or decarboxylase inhibitor) (next column; L-D), at the time of their maximum response to single doses of CY 208-243 (5-40 mg orally). Solid circles indicate scores at times when the patients were judged by their attending doctor to be off (i.e., akinetic and rigid). Open circles are scores when the patients were clearly on (i.e., mobile). The half-circles for two patients indicate a score at a time when the patient was intermediate between on and off. 1 zyxwvu 0 40 t 0 * * 0 . 0 zy zy zyxwvut Movement Disorders, Vol. 4 , N o . 3. 1989 20 0 0 0 O 8 I 6 L-D 5 20 mgCY 10 40 zyxw zy zyxw ANTIPAR K l N S O N l A N ACT1VIT Y OF C Y 208-243 265 activity. In addition, the formation of metabolites that interfere with dopamine receptors might account for the lack of efficacy of SKF 38393. CY 208-243 is not known to possess significant D, receptor agonist activity. The present results of administration of CY 208-243 to parkinsonian marmosets and humans suggests that D, receptor stimulation can reverse the akinetic-rigid syndrome. If optimum antiparkinsonian treatment requires an appropriate balance between D, and D, receptor Stimulation, further studies with CY 208-243 may indicate methods of improving the clinical response to drug treatment of Parkinson’s disease. zyxwvut zyxw zyxwvu zyxwv zyx zyxwvuts REFERENCES I . Schachter M. Bedard P, Debono AG. et al. The role of D-l and D-2 receptors. Nrirrrre 1980286: 157-9. 2. Starke K, Spaeth JD. Adelung C. Further functional in vitro comparison of pre- and post-synaptic dopamine receptors in the rabbit caudate nucleus. Nor{tt\n Sc/itnirdeher,ys Arch Phrir-mrrcol 1983;323:298-306. 3. Markstein R. Seiler MP, Vigouret J M , Urwyler S. Eng A , Dixon K. In: Sandler M. ed. Progress in crrrecholri/nine resetrrclt. ce~irrrrltrspecrs. New York: Allan Liss (in press). 4. Fahn S , Elton RL. et al. The unified Parkinson’s disease Rating Scale. In: Fahn S , Marsden CD, Calne D. Goldstein M, eds. Recenr dewlopmenrs in Ptrrkimon’s diwcise. Vol. If. New Jersey: Macmillan Healthcare Information. 1987: 153-64. 5. Close SP, Marriott AS. Pay S. Failure of S K F 38393-A to relieve parkinsonian symptoms induced by I-methyl-Cphenyl-1.2.3.6-tetrahydropyridine in the marmoset. Br J Phrrrmucol 1985;85:32%2. 6 . N o m o t o M. Jenner P. Marsden CD. The dopamine D-2 agonist L Y 141865. but not the D-l agonist SKF 38393, reverses parkinsonism induced by l-methyl-4-phenyl-l.7-.3.6-tetrahydropyridine (MPTP) in the common marmoset. Neirrosci Left 1985:57:3731. 7. Braun A, Fabbrini G. Mouradian M M , Serrati C, Barone P. Chase TN. Selective D-1 dopamine receptor agonist treatment of Parkinson‘s disease. J Nero-ti/ Trtrnsm 1987;68:41-50. Movement Disorders. Vol. 4 , No. 3 . 1989