Progress in the medicinal chemistry of dopaminergic agents.

Ergot alkaloids and their derivatives have long been recognized for their potent pharmacologic activity. A number of ergot derivatives, including the dopamine agonists bromocriptine and pergolide, are currently in clinical use for the treatment of CNS and endocrine disorders. In an effort to develop more selective dopamine agonists, studies were directed to elucidate the dopaminergic pharmacophore of the ergoline nucleus. During the course of this work, it was found that the tricyclic system containing only the B-, C-, and D-rings of the ergoline skeleton (2, X = CH) possessed D-2 dopamine agonist activity. As a result of this discovery, interest was stimulated in the preparation of other heteroareno[g]quinoline systems (3, "BCD partial ergolines") for investigation of their dopaminergic properties. Factors which we found to be particularly important in determining dopaminergic activity were: (1) the nature of the heteroaromatic B ring; (2) the orientation of that heteroaromatic ring; (3) the substituents on the heteroaromatic ring; and (4) the relative and absolute stereochemistry at the CD ring fusion. We report here the synthesis and pharmacologic activity of a series of BCD partial ergolines (3) and describe how the study of these new compounds allows for the delineation of structural features important in D2 dopamine receptor activation.

Synthesis and pharmacology of a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids. Potent N-methyl-D-aspartate receptor antagonists.

We recently prepared a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated for their ability to displace [3H]CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists). Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced [3H]CPP binding with IC50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively. The rest of the compounds prepared were weakly active or inactive in these assays. The pattern of activity observed for this series parallels that observed for the acyclic series of omega-phosphono-alpha-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive. Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.