Dopamine agonists structural modeling

Recent data in our laboratories indicated the possible involvement of central and peripheral dopamine binding sites in the pathogenesis of duodenal ulceration. Structure activity studies with duodenal ulcerogens implicated dopamine as a putative mediator and/or modulator in duodenal ulceration. Using the cysteamine- or propionitrile-induced duodenal ulcer model in rats, we found that dopamine agonists (e.g., bromocriptine, lergotrile,... 

To help characterize the structure and function of dopamine receptors at the molecular level, the x-ray crystal structure of apomorphine (77) was compared to a structural model of dopamine ("Fig. 25.9k It is obvious that apomorphine contains molecular features In common with the structure of dopamine In the trans a-rotamer conformation ("Figs. 25.9 and 25. 0). Isoapomorphine, which embeds the structure of dopamine In the trans p-rotamerlc conformation ("Fig. 25.10k Is less active than apomorphine as a dopamine agonist. The... 

Through the years a number of different structure-activity relationships (SARs) and receptor models have been developed (for reviews see refs. 91, 92). Therefore this introduction will only give a short overview of the general aspects of dopamine receptor agonist SARs. 

Several plants produce compounds which are identical to animal neurotransmitters, such as acetylcholine and histamine in stinging hairs of Urtica, or serotonin and dopamine in several other species (Tables 3-9). That these compounds can serve as receptor agonists is apparent. Furthermore, quite a number of alkaloids are known whose structures share obvious structural elements with endogenous neurotransmitters (compare neurotransmitters in scheme I with alkaloids in II) and could thus function as structural analogues. If the three dimensional structure of the corresponding receptor or protein were known, the methodology of molecular modeling could be employed. This approach was not in the... 

Seiler, M.P., Floersheim, P., Markstein, R. and Widmei A. (1993) Structure-activity relationships in the ra s-Hexahydroindolo[4, 3- f>]phenanthridine ( Benzergoline ) series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective Dj agonist CY 208-243 and its implification for an extended rotamer-based dopamine receptor model ./. Med. Chem., 36, 977-984. 

---