Effector selective intrinsic activity of novel dopamine agonists at the D-2 dopamine receptor

The pharmacological manipulation of central dopamine neurotransmission plays a critical role in the clinical treatment of many neurologic, neuroendocrine, and psychiatric disorders. In particular, the development of dopamine ligands having high affinity and selectivity for the D{dollar}sb2{dollar}-like pharmacological class of dopamine receptors (comprised of the D{dollar}sb2,{dollar} D{dollar}sb3,{dollar} and D{dollar}sb4{dollar} molecular isoforms of the receptor) has contributed significantly to the effective treatment of psychotic disorders, neurodevelopmental disorders, Parkinson's disease, and pituitary prolactinomas. Dopamine neurons are concentrated in mesencephalic nuclei and are also present in the hypothalamus and retina. The major terminal projections are to the nuclei of the basal ganglia (mesostriatal), the nucleus accumbens (mesolimbic), the entorhinal and prefrontal cortices (mesocortical), and the pituitary (tuberoinfundibular/tuberohypophyseal). D{dollar}sb2{dollar}-like receptors couple to inhibitory G proteins to exert effects on adenylyl cyclase activity, phosphoinositide turnover, and ion flux through potassium and calcium channels. Through these biochemical effects, D{dollar}sb2{dollar}-like receptors modify cellular functions such as neurotransmitter/neurohormone release. The functional expression of D{dollar}sb2{dollar}-like receptors in the brain is regionally heterogeneous and appears to be determined in a cell-specific manner. D{dollar}sb2{dollar}-like ligands that selectively activate functional sub-populations of the receptor (e.g., active at D{dollar}sb2{dollar}-like receptors coupled to adenylyl cyclase but inactive at D{dollar}sb2{dollar}-like receptors coupled to potassium ion channels) have not been reported. The following work describes studies demonstrating that the novel hexahydrobenzo (a) phenanthridine class of dopamine agonists have an apparent selectivity for D{dollar}sb2{dollar}-like receptors coupled to adenylyl cyclase activity, which is potently and dose-dependently inhibited by these agonists. At D{dollar}sb2{dollar}-like receptors coupled to inwardly rectifying potassium ion channels, this same class of agonists demonstrates low intrinsic activity and, at best, partial agonist functional effects (Smith et al., 1995). This unusual pharmacology may explain the apparent lack of D{dollar}sb2{dollar}-like autoreceptor effects observed in vivo and in vitro (Mottola et al., 1992). Since autoreceptor effects negatively regulate dopaminergic function, this class of agonists is predicted to have superior clinical efficacy in hypoactive dopaminergic diseases, such as Parkinson's disease. Understanding the molecular determinants of agonist effector selectivity would also provide a rational basis for designing effector selective ligands to other G protein coupled receptor systems (such as serotonin and adrenergic systems).