Bimxganic & hledicid &mis~ry getters, ~01.3. No.8, pp. 1477-1483.1993 Priited in Great Britain 0960-894x193 $6.00 + .c@ 0 1993 Pcrgmon Press Ltd Dopamine Autoreceptor Agonists: Computational Studies, Synthesis and Biological Investigations zyxwvutsrqponmlkjihgfed Peter Gmeiner *, Josef Sommer, Joachim Mierau $ and Georg HSfner Institut fiir Pharmazie und Lebensmittelchemie der Ludwig- Maximilian.+Universitit, SophienstraBe 10, 8000 Munchen 2, Germany $ Abteilung Biochemische Forschung, Boehringer Ingelheim KG, 65@7 lngelheim / Rhein, Germany (Received zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA in Belgium 1 M arch 1993; accepted 24 April 1993) Abstract: Based on molecular modeling studies on the electronic properties of dopamine and dopamine agorusts the pyraz.o10[1,5-alpyridine structure has been evaluated as a catechol surrogate. The azaergoline analogue 6, including this moiety has been synthesized via 1,3-dipolar cycloaddition, anionic ring closure and electrophilic amination. The target compounds (6) exhibit DA autoreceptor agonistic activity. Presynaptic dopamine receptors serve an inhibitory feed back function on dopaminergic neurotransmissi0n.l Functionally, stimulation of the D-2 autoreceptor inhibits dopamine (DA) synthesis, release and DA neuronal firing. Since schizophrenia is associated with hyperactivity in the mesolimbic system (A 10 system) application of selective DA autoreceptor agonists is a very promising approach to a new class of neuroleptic drugs. * These atypical neuroleptics may offer a more subtle neurotransmitter regulation than the classical neuroleptics with D-2 antagonistic properties. As a consequence, considerable efforts have been dedicated to the design and synthesis of DA autoreceptor agonists without appreciable activity at the postsynaptic DA receptors resulting in compounds as (-)-3-PPP,3 EMD 2344g4 BHT 920 (talipexole) 5 and SND 919 (pramipexole).6 Since it is assumed that the binding sites of the postsynaptic D-2 receptor and its presynaptic analogues are very similar,7 it seemed to be a valuable strategy to modify the structure of known D-2 receptor agonists. We have previously reported that the (S)-enantiomer of the aminotetrahydroindolizine 1 strongly reduces DA synthesis, causes sedation in mice and reveals strong and selective affinity to the D-2 receptor, labeled with the selective autoreceptor agonist SND 919.* On the other hand the regioisomer 2 exhibits only a low order of dopaminergic effects. Thus, structural manipulation of the aromatic moiety seems to be very promising but also very sensitive. 1 and 2 are structurally related to the DA agonistic isoindole derivative 3, which is assumed to be the pharmacophoric core-structure of the ergolines (4).9 Based on these observations, we here report on molecular design, synthesis and tricyclic ergolines 5.9 pharmacological investigations of analogues of the DA active 1477