In the further development of CNS
dopamine autoreceptor active compounds related to
3-PPP, the transfused
7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline HW-165 and its enantiomers were synthesised. This paper describes the basic pharmacological properties of these latter, novel "atypical"
dopaminergic agents, based on an extensive series of biochemical and behavioural experiments in rats. By and large, the pharmacological activities of
HW-165 - essentially, if not exclusively, residing in its (4aS,10bS)-(-)-enantiomer - were similar to those displayed by (S)-(-)-3-PPP, indicating the simultaneous presence of central
dopamine (
autoreceptor) agonist and weak (postsynaptic) antagonist properties in the molecule. Thus, in non-pretreated animals
HW-165 and its active species monotonically suppressed the spontaneous locomotion without causing
catalepsy or other appreciable motor disabilities, and at the same time selectively reduced the
dopamine synthesis, release/turnover and utilisation. Some differences in these biochemical responses to
HW-165 [racemate or (-)-enantiomer] were, however, noted in the limbic vs. striatal brain areas (e.g. decrease of
dopamine synthesis particularly in the limbic parts). On the other hand, while failing to reverse
reserpine-induced akinesia or to elicit stereotyped behaviour, the agents markedly inhibited the
dopamine synthesis in either of the
dopamine-dominated cerebral regions in the reserpinised as well as in
gamma-butyrolactone (GBL)-treated rats. As shown for racemic
HW-165 after
reserpine pretreatment, the inhibition of
dopamine synthesis was completely and stereoselectively blocked by (+)-
butaclamol, thereby supporting direct
dopamine receptor interaction. Racemic
HW-165 readily antagonised the
d-amphetamine-induced locomotor hyperactivity.
Apomorphine-induced hyperactivity was, however, distinctly more resistant to antagonism by
HW-165 [racemate or (-)-enantiomer]. Moreover, the latter agents fully prevented the
apomorphine-induced inhibition of striatal
dopamine synthesis in otherwise non-pretreated rats, while only partly counteracting this effect of
apomorphine in the limbic regions of such animals, and in either brain area of rats treated with gamma-butyro-
lactone. The findings are interpreted within the context of the mixed
dopamine agonist/antagonist properties (referred above) of
HW-165 and its active (-)-species in relation to the adaptive state of central
dopamine receptors and possible regional variations in feedback strength and organisation.(ABSTRACT TRUNCATED AT 400 WORDS)