title: Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset.
abstract: In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D1 DA receptor selectivity), demonstrated high D1 DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) and SKF 75670 (3-CH3 analogue) further reduced locomotor activity (by -70 to -80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6-10 fold) and a reversal in motor disability (by -64 to -77%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D2 DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D1 DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D1 DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D1 DA receptors uncoupled to AC and/or a role for extrastriatal D1 DA receptors in mediating the behavioural response to D1 DA agonists.
authors.affiliation: Parkinson's Disease Society Experimental Research Laboratories, King's College London, UK.
authors.forename: K K
authors.initials: KK
authors.lastname: Gnanalingham
authors.forename: D D
authors.initials: DD
authors.lastname: Erol
authors.forename: A J
authors.initials: AJ
authors.lastname: Hunter
authors.forename: L A
authors.initials: LA
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Jenner
authors.forename: C D
authors.initials: CD
authors.lastname: Marsden
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002144:Callithrix; D018491:Dopamine Agonists / Q000378:metabolism / Q000627:therapeutic use*; D004873:Ergolines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D019257:Quinpirole; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D004873:Ergolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D013134:Spiperone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine