Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat—relationship to circling behaviour

Q2 · MEDICINE

Article

Author: Peter Jenner ; C.David Marsden ; Kanna K. Gnanalingham ; A.Jackie Hunter

The ability of benzazepine D-1 dopamine agonists with varying efficacies in stimulating adenylate cyclase and to induce contralateral circling was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats, the benzazepines SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue), SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue), all produced contralateral circling. The rank order of efficacies (maximal effect, Emax) being, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 >> SKF 82958. In striatal slices from the intact hemisphere, dopamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclase activity. The rank order of efficacies being SKF 82958 (109%) = dopamine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 (67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylate cyclase activity, this effect did not reach statistical significance. In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenylate cyclase activity were lower (-25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denervated striatum was greater than observed in the intact striatum. The rank order of efficacies in the dopamine denervated striatum being SKF 82958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SKF 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepine derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circling and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 dopamine receptors and/or transduction systems other than adenylate cyclase.

01 Feb 1995·PsychopharmacologyQ3 · MEDICINE

Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset

Q3 · MEDICINE

Article

Author: Lance A. Smith ; Dilek D. Erol ; C. David Marsden ; Peter Jenner ; A. Jackie Hunter ; Kanna K. Gnanalingham

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.

01 Apr 1993·Behavioural PharmacologyQ4 · PSYCHOLOGY

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

Q4 · PSYCHOLOGY

Article

Author: Bond, B. ; Overend, P. ; Reavill, C. ; Hunter, A. J.

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Discovery	GB	Smithkline Beecham Pharmaceuticals (India) Ltd.	-

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