trans-hexahydroindolo[4,3-ab]phenanthridines ("benzergolines"), the first structural class of potent and selective dopamine D1 receptor agonists lacking a catechol group.

In contrast to the many selective dopamine (DA) D2 receptor agonists known, only two prototypes of selective D1 receptor agonists have been described; both show preference for the periphery due to their catechol partial structures. Our search for non-catechol, selective D1 agonists was based on the hypothesis that D1 selectivity could be conferred upon ergolines by annulation with a phenyl ring. The target molecules, trans-4,6,6a,7,8,12b-hexahydroindolo-[4,3-ab]phenanthridi nes ("benzergolines"), were efficiently synthesized by using the Ninomiya enamide photocyclization reaction. These compounds were found to be as active as the most potent D1 agonists in the adenylate cyclase D1 receptor model, but showed no activity in the ACh release D2 receptor assay. The acquired subtype selectivity of the novel structures was accompanied by an enhanced potency and efficacy as compared to the corresponding ergolines. This points to a D1 affinity enhancing, D2 receptor discriminating role for the additional phenyl group and provides further support for the existence of a D1 receptor specific accessory aryl binding site. Thus the benzergolines represent the first structural class of potent and selective D1 agonists lacking a catechol group which should allow an efficient central nervous system penetration. On the basis of these results, the D1 agonist pharmacophore has to be revised in the sense that potent activity requires neither a catechol function nor an orthogonal conformation of the aromatic rings.

CY 208-243: a unique combination of atypical opioid antinociception and D1 dopaminomimetic properties.

Here we describe the potent antinociceptive action of the indolophenanthridine, CY 208-243, which has high affinities to the dopamine D1 binding and the opioid sites as well as to the 5-HT1A site. The antinociceptive action was comparable to that of morphine in most, but not all models of nociception, nevertheless, basic differences exist in its overall profile. Antagonism of CY 208-243's antinociceptive action was only possible with either high doses of naloxone or not at all and no cross-tolerance with morphine in CY 208-243 tolerant rats occurred. The biochemical basis for dependence liability may be absent and no opioid activity was observed in cultured hippocampal cells. Physical dependence did not occur after programmed administration in the rhesus monkey, nor did CY 208-243 cause respiratory depression in the rat (rather a stimulation). Lack of generalization in fentanyl-trained rats strongly suggests that CY 208-243 lacks opioid-like subjective cues. The coexistence of D1 dopaminergic and atypical opioid agonist properties represents a unique pharmacodynamic combination which is not shared with any other analgesic, and may provide safe and innovative pain therapy.

Pitrazepin, a novel GABAA antagonist.

Pitrazepin is a potent new GABA antagonist which differs from bicuculline in its chemical structure and its interaction with both [3H]muscimol and [3H]flunitrazepam binding sites, whereby the potency of pitrazepin in displacing [3H]muscimol exceeds that of bicuculline by at least a factor of 10. In physiological experiments, blockade of synaptically released GABA by pitrazepin was shown to reduce inhibitory postsynaptic potentials and resulted in the onset of bursting activity which persisted for hours following drug application. The effect of pitrazepin was not tissue specific since it induced a bursting discharge pattern in cultures derived from hippocampus and hypothalamus. Bursting activity was abolished by GABA, baclofen and pentobarbital, but only weakly reduced by midazolam. Pitrazepin also antagonized the action of exogenous GABA, but failed to influence the action of baclofen, an effect which was associated with a decreased membrane input resistance and which was blocked by barium. These results indicate that pitrazepin selectively interacts with the putative GABAA site, thereby antagonizing the chloride-dependent GABA response.