The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the ␤ 2 -adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts. Receptor Pharmacology for the New MillenniumFor the last half-century, pharmacological theory has posited that ligands could be characterized by the nature of the functional effects elicited by their interaction with their tar-

Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D 2 -dopamine receptors and relatively high affinities for 5-HT 2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D 2 -dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT 2B -, hD 2L -, and hD 3 -dopamine receptors, but also has significant affinity

cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

The apolipoprotein E (APOE) ε2 allele has been associated with both Parkinson's disease (PD) and lower low density lipoprotein cholesterol (LDL-C). The study is to test the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 110 controls, the PD cases recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and controls recruited from the spouse populations of the same clinic. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterollowering agents. Lower LDL-C concentrations were associated with a higher prevalence of PD. Compared with participants with the highest LDL-C (≥139 mg/dL), the OR was 2.2 (95% CI 0.9-5.1) for participants with LDL-C of 115-138, 3.5 (95% CI 1.6-8.1) for LDL-C of 93-114, and 2.6 (95% CI 1.1 -5.9) for LDL-C ≤ 92. Interestingly, use of cholesterol lowering drugs or just statins was related to lower PD prevalence. Our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence; either of which findings warrant further investigations. KeywordsParkinson's disease; LDL cholesterol; apolipoprotein E; statin; case control study Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder affecting 1-2% of the population over the age of 60 years. The lifetime risk for PD is higher in men than in women. 1 Although a few PD cases are due to several known genetic mutations, the disorder is largely idiopathic, and likely involves interactions of the genome and the environment 2 .The role of apolipoprotein (APOE) in Alzheimer's disease (AD), another age-related neurodegenerative disease, has been elucidated in the past decade. It is generally believed that the ε4 allele is a major susceptibility gene, whereas the ε2 allele is protective for AD and possibly other neurological disorders see review 3 . A recent systematic review, however, Previous epidemiological evidence on dietary fats/cholesterol and PD risk has not been consistent. 10;11 Further, these studies are not directly relevant to the potential role of cholesterol in PD etiology, as non-dietary factors may play more important roles in regulating serum lipid levels. For example, the APOE ε4 allele has been associated with higher low density lipid cholesterol (LDL-C), whereas the ε2 allele has been consistently associated with lower plasma LDL-C. 12;13 Interestingly, there has been one published abstract reporting lower plasma cholesterol concentrations in PD patients than in controls. 14 Further, Musanti et al. 15 reported dramatically lower cholesterol biosynthesis in PD patients than in controls, although there has been no subsequent follow up on this association. The above evidence, coupled with the association between ε2 and PD, led us to test hypothesis that lower serum LDL-C may be ass...

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D 2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D 2 and 5-HT 2A antagonists, and those that also bind with modest affinity to D 2 , 5-HT 2A , and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D 2 partial agonism or D 2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D 2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D 2 antagonists.Keywords functional selectivity; antipsychotic drugs; schizophrenia; receptor mechanisms; G protein-coupled receptors; dopamine receptors; serotonin receptors; drug action A. The first two generations of antipsychotic drugsThe serendipitous observations about antipsychotic actions of chlorpromazine [1] ultimately led to the finding that these antipsychotic effects were due to antidopaminergic actions [2]. Numerous antipsychotics were subsequently developed that, like chlorpromazine, work primarily as dopamine D 2 receptor antagonists. Drugs of this type (first called typical and now named first generation antipsychotics) include a variety of different chemical classes. These NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Curr Pharm Des. 2010 ; 16(5): 488-501. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript typical drugs can be classified as high, intermediate, or low potency based on their average daily dose range, with their clinical potency often highly correlated with their affinity for the dopamine D 2 receptor [3]. Thus, actions at dopamine systems have been a critical mechanism in all currently approved antipsychotic drugs and many of the compounds in the discovery and development pipeline. Dopamine systems and their rece...

Aripiprazole is a unique atypical antipsychotic drug with an excellent side-effect profile presumed, in part, to be due to lack of typical D 2 dopamine receptor antagonist properties. Whether aripiprazole is a typical D 2 partial agonist, or a functionally selective D 2 ligand, remains controversial (eg D 2 -mediated inhibition of adenylate cyclase is system dependent; aripiprazole antagonizes D 2 receptormediated G-protein-coupled inwardly rectifying potassium channels and guanosine triphosphate nucleotide (GTP)gS coupling). The current study examined the D 2L receptor binding properties of aripiprazole, as well as the effects of the drug on three downstream D 2 receptor-mediated functional effectors: mitogen-activated protein kinase (MAPK) phosphorylation, potentiation of arachidonic acid (AA) release, and D 2 receptor internalization. Unlike quinpirole (a full D 2 agonist) or (À)3PPP (S(À)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, a D 2 partial agonist), the apparent D 2 affinity of aripiprazole was not decreased significantly by GTP. Moreover, full or partial agonists are expected to have Hill slopes o1.0, yet that of aripiprazole was significantly 41.0. Whereas aripiprazole partially activated both the MAPK and AA pathways, its potency vs MAPK phosphorylation was much lower relative to potencies in assays either of AA release or inhibition of cyclic adenosine 3 0 ,5 0 -cyclic monophosphate accumulation. In addition, unlike typical agonists, neither aripiprazole nor (À)3PPP produced significant internalization of the D 2L receptor. These data are clear evidence that aripiprazole affects D 2L -mediated signaling pathways in a differential manner. The results are consistent with the hypothesis that aripiprazole is a functionally selective D 2 ligand rather than a simple partial agonist. Such data may be useful in understanding the novel clinical actions of this drug.

Background Parkinson’s disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. Methods Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, and III sub-scores, and levodopa-equivalent daily dosage. All studies were done while PD patients were “on drug.” Results Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm3) and left (164 mm3) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm3) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. Conclusion The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD.

This large study suggests that long-term smoking is more important than smoking intensity in the smoking-Parkinson disease relationship.