Dyskinesia affects the majority of levodopa-treated parkinsonian patients within 5–10 years of treatment with levodopa. Clinical and preclinical observations suggest that an increase in serotoninergic transmission can contribute to the appearance of dyskinesias. It is thus conceivable that a modulation of synaptic dopamine (DA) levels induced by the inhibition of serotonin (5-HT) release, as a consequence of 5-HT1A agonists administration, might alleviate dyskinesias.

Type 1 diabetes most commonly presents in adulthood, contrary to the widely held view that it is a disease of childhood. Furthermore, a substantial proportion of cases of adult-onset type 1 diabetes does not require insulin therapy at clinical onset. Recent studies have emphasised the evidence that adult-onset type 1 diabetes is prevalent but often misclassified initially as type 2 diabetes (1, 2). In this review, we discuss that recent literature, highlighting the similarities and differences between adult-onset and childhood-onset type 1 diabetes, exploring recent debates surrounding its epidemiology and genetics, as well as expanding on important issues of diagnostic criteria for individuals presenting with adult-onset diabetes and the subsequent management once identified as having an autoimmune basis. In addition, this review looks at the psychosocial challenges faced by T1D patients and their possible management.

AIMS/HYPOTHESIS:We investigated spinal and peripheral kappa opioid systems in diabetic rats.MATERIALS AND METHODS:Dynorphin A, N-methyl-D-aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting. Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline.RESULTS:Dynorphin A protein levels were significantly increased in peripheral nerves and footpad skin of diabetic rats. Dynorphin A exhibits both anti- and pro-nociceptive properties depending on activation of either KOR or NMDA receptors. Spinal protein levels of these receptors were not changed by diabetes, while KOR levels in the sciatic and peroneal nerves were significantly increased. Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats. Both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats were acutely ameliorated by asimadoline. To confirm that the effect of asimadoline was related to its property as KOR agonist, diabetic rats were pretreated with the selective KOR antagonist nor-binaltorphimine. Intraplantar nor-binaltorphimine abolished the ability of asimadoline to alleviate tactile allodynia in diabetic rats. Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats.CONCLUSIONS/INTERPRETATION:Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

Dyskinesia is the most troublesome side effect in long-term treatment of both Parkinson's disease (PD) and schizophrenia. The 5-HT1A agonist and D3/D4 ligand sarizotan [Bartoszyk, G.D., van Amsterdam, C., Greiner, H.E., Rautenberg, W., Russ, H., Seyfried, C.A., 2004. Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J. Neural Transm. 111, 113-126.] is in clinical development for the treatment of PD-associated dyskinesia. Because 5-HT1A agonists are known to counteract antipsychotic-induced motor side effects, sarizotan was investigated for its effects in two rat models of tardive dyskinesia (TD). The acute administration of sarizotan (0.17-13.5 mg/kg i.p.) reduced episodes of SKF 38393-induced repetitive jaw movements (RJM) in rats with a maximal effect at 1.5 mg/kg. In a chronic study, sarizotan (0.04-9 mg/kg/day), administered in the drinking water for 7 weeks during withdrawal from chronic haloperidol treatment (1.5 mg/kg/day), dose-dependently reversed haloperidol-induced RJM, significant at the doses of 1.5 and 9 mg/kg. Agonism at 5-HT1A receptors may be mediating the inhibitory effect of sarizotan on RJM in rat models of tardive dyskinesia.

The effect of vilazodone, a putative selective serotonin re-uptake inhibitor (SSRI) with 5-HT (5-hydroxytryptamine)(1A) receptor partial agonist activity, was investigated on 5-HT efflux and 5-HT re-uptake half life in the guinea-pig dorsal raphe nucleus, using in vitro fast cyclic voltammetry. The SSRI, fluoxetine, significantly increased 5-HT efflux. In contrast, vilazodone had no effect on 5-HT efflux at 100 nM but significantly decreased 5-HT efflux at 1 microM. Co-perfusion of 8-OH-DPAT (+/-8-hydroxy-2-(di-n-propylamino)tetralin) with fluoxetine significantly attenuated the fluoxetine-induced increase in 5-HT efflux. Co-perfusion of WAY 100635 with vilazodone did not attenuate the effect of vilazodone alone. In addition, the re-uptake half life for 5-HT was significantly increased by both fluoxetine and vilazodone. In conclusion, we have demonstrated that vilazodone (100 nM, 1 microM), in the guinea-pig dorsal raphe nucleus, blocks the serotonin transporter but does not display 5-HT(1A) receptor agonism.

Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.) dose-dependently displaced in vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.

The effects of sarizotan, a 5‐HT1A agonist with additional affinity for D3 and D4 receptors, have been studied on the corticostriatal glutamate pathways using dual‐probe microdialysis in the awake rat. Sarizotan given systemically (0.1–10 mg/kg s.c.) or perfused into the motor cortex (10 μM) produced 20–30% reduction of cortical and striatal glutamate levels. The inhibitory effects of the systemic sarizotan on cortical and striatal glutamate levels were counteracted by intracortical perfusion with the 5‐HT1A antagonist WAY100135 (10 μM). These findings suggest that the antidyskinetic properties of sarizotan could be mediated via its 5‐HT1A agonist actions in the motor cortex, leading to reduced activity in the corticostriatal glutamate pathways with reduced activation of the striatopallidal GABA pathway mediating motor inhibition. Synapse 58:193–199, 2005. © 2005 Wiley‐Liss, Inc.

Fluorine substitution modifies structural attributes and often induces unexpected effects. When substituting fluorine with cyano in position 5 of the indole in indole-butyl-amines, the properties of the compounds proved to be very comparable. In vitro target-profile, metabolism, and in vivo activity in the ultrasonic vocalisation test indicate bioisosterism between the two substituents.

A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT(1A) agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT(1A) affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D(2) binding and increased selectivity for the 5-HT(1A) receptor. Agonistic 5-HT(1A) receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-[4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 4.7 nM] with nanomolar 5-HT(1A) affinity [IC(50) = 0.9 nM] and selectivity [D(2), IC(50) > 850 nM]. 3-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT(1A) agonists known [5-HT(1A), IC(50) = 0.09 nM; D(2), IC(50) = 140 nM].

Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT(1A) receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT(1A) receptor affinity and to suppress D(2) receptor binding. 5-[4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl]benzofuran-2-carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 1.1 nM] with subnanomolar 5-HT(1A) affinity [IC(50) = 0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI = 0.5 nM] showing a great selectivity to other GPCRs (e.g., D(2), IC(50) = 666 nM).

The potent κ-opioid receptor agonist n-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl]-2,2-diphenyl-acetamide hydrochloride (asimadoline, EMD 61753) was initially developed for the treatment of chronic pain. Because opioids are well known to reduce secretion and to cause constipation, we investigated the effects on epithelial transport in murine trachea and colon. In Ussing chamber experiments, asimadoline (100 μM) decreased short-circuit currents in airways and colon epithelium. The inhibition of ISC was not blocked by naloxone (10 μM) or nor-binaltorphimine (10 μM), suggesting that the response was not mediated by κ-opioid receptors. The effect of asimadoline on ISC was concentration-dependent with half-maximal inhibition of ISC at 23.7 (9.5–49.3) μM and was sensitive to the K+ channel blocker charybdotoxin (10 nM). The amiloride-sensitive Na+ current was reduced by asimadoline, but not in cAMP stimulated tissues. Asimadoline strongly inhibited transient Ca2+-dependent Cl− secretion, activated by the muscarinic receptor agonist carbachol (100 μM) or the purinergic agonist ATP (100 μM). Thus, asimadoline inhibits epithelial transport independent of κ-opioid receptors, by inhibition of basolateral Ca2+-activated and charybdotoxin-sensitive K+ channels.

The dual serotonin (5-HT) re-uptake inhibitor and 5-HT1A receptor agonist vilazodone was found to increase central serotonin levels in rat brain. In the course of structural modifications of vilazodone 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl}-1H-indole-5-carbonitrile 8i and its fluorine analogue 6-{4-[4-(5-fluor-3-indolyl)-butyl]-1-piperazinyl}-2H-1-benzopyran-2-one have been identified. These unsubstituted chromenones are equally potent at the 5-HT1A receptor and 5-HT transporter. The implementation of nitrogen functionalities in position 3 of the chromenones resulted in compounds acting as agonists at the 5-HT1A receptor and as 5-HT re-uptake inhibitors like vilazodone. Ex vivo 5-HT re-uptake inhibition and in vitro 5-HT agonism were determined in the PCA- and GTRgammaS-assay, respectively. The potential of these chromenones to increase central 5-HT levels was measured in microdialysis studies and especially the derivatives 3-{4-[4-(3-amino-2-oxo-2H-chromen-6-yl)-piperazin-1-yl]-butyl-1H-indole-5-carbonitrile 8f, ethyl (6-{4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl}-2-oxo-2H-chromen-3-yl)-carbamate 8h and N-(6-{4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl}-2-oxo-2H-chromen-3-yl)-acetamide 8k give rise to rapid development of increased serotonin levels in rat brain cortex, lasting longer than 3h. (C) 2004 Elsevier Ltd. All rights reserved.

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.