2-like Receptor Research Articles

Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: An animal model

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n = 10), a selective M 3 muscarinic antagonist; ketanserin 2 mg/kg (n = 10), a 5HT 2A antagonist; raclopride 0.3 mg/kg (n = 11) a selective D 2/D 3 antagonist; terfenadine 20 mg/kg (n = 9) a selective H 1 antagonist; or, vehicle (n = 11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H 1 blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M 3) and serotonergic (5HT 2) antagonism on insulin secretion. Based on the expression of D 2-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D 2 blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.

Synthesis and characterization of selective dopamine D 2 receptor ligands using aripiprazole as the lead compound

A series of compounds structurally related to aripiprazole ( 1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D 2-like dopamine receptors. These compounds also share structural elements with the classical D 2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1 H)-one oxalate ( 6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1 H)-one oxalate ( 7) were found to (a) bind to the D 2 receptor subtype with high affinity ( K i values <0.3 nM), (b) exhibit >50-fold D 2 versus D 3 receptor binding selectivity and (c) be partial agonists at both the D 2 and D 3 receptor subtype.

The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model

The present study examined the roles of dopamine and D 1- and D 2-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(−)-apomorphine hydrochloride, 1.0, 2.5 and 5.0 μg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D 2-like dopamine receptor antagonist S(−)-raclopride(+)-tartrate salt (raclopride, 3.0 μg), but not by the D 1-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0 μg). Apomorphine-induced antinociception was mimicked by microinjection of the D 2-like dopamine receptor agonist (−)-quinpirole hydrochloride (2.0 and 5.0 μg) into the same VLO site, and this effect was antagonized by raclopride (3.0 μg). In addition, microinjection of the D 1-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0 μg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D 1-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10 μg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D 2-like receptors mediated dopamine-induced antinociception, while D 1-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D 1-like dopamine receptors could induce antinociception.

An analysis of nicotine conditioned place conditioning in early postweanling and adolescent rats neonatally treated with quinpirole

This study investigated nicotine place conditioning in early postweanling and adolescent male and female rats neonatally treated with quinpirole, a dopamine D 2/D 3 agonist. Previous research has shown that neonatal quinpirole treatment results in an increase of dopamine D 2-like receptor sensitivity that persists throughout the animal's lifetime, relevant to psychosis. Rats were neonatally treated with quinpirole or saline from postnatal day (P)1-21, and animals were conditioned with nicotine or saline daily from P23-30 as early postweanlings or P32-39 as adolescents in a two- or three-chambered place conditioning apparatus. A drug free test was given on P31 for early postweanlings, and P40 for adolescents. Results on the two chamber apparatus revealed that nicotine increased time spent in the drug-paired context at both ages tested. Neonatal quinpirole treatment resulted in less time spent in the drug-paired context in early postweanling males and increased time spent in the drug-paired context in adolescent females conditioned with nicotine. Adolescent females neonatally treated with saline and conditioned with nicotine on the two chamber apparatus did not differ from controls. On the three-chambered apparatus, nicotine increased time spent in the drug-paired context in both ages tested, which was blocked by neonatal quinpirole in early postweanling males, but enhanced by neonatal quinpirole treatment in adolescents. These results demonstrate both age and sex differences in the effects of nicotine and point to significant differences in performance depending on the apparatus used. Additionally, neonatal quinpirole enhanced the effects of nicotine, but this is true only in adolescents and task-dependent.

CAMP Response Element Binding Protein Phosphorylation in Nucleus Accumbens Underlies Sustained Recovery of Sensorimotor Gating Following Repeated D 2-Like Receptor Agonist Treatment in Rats

Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits are observed in humans and rats upon acute treatment with dopamine D₂-like receptor agonists and in patients with schizophrenia. Repeated treatment with a D₂-like agonist, however, reverses PPI deficits and increases cyclic adenosine monophosphate (cAMP) signaling in the nucleus accumbens (NAc). This study examined the short- and long-term effects on PPI of treatment with quinpirole and ropinirole, dopamine D₂/D₃ receptor agonists, and the molecular mechanism by which they occur. PPI was assessed in adult male Sprague-Dawley rats following acute and chronic treatment with quinpirole or ropinirole and 1, 2, 3, and 4 weeks after termination of repeated ropinirole treatment. Finally, the effect of dominant negative mutant cAMP response element binding protein (CREB) overexpression in the NAc on PPI following chronic quinpirole treatment was assessed. Acute quinpirole produced dose-dependent PPI deficits, whereas ropinirole caused consistent PPI reduction at all but the highest dose. Repeated ropinirole treatment significantly increased PPI compared with acute treatment, and increased CREB phosphorylation in NAc neurons. Subsequent ropinirole challenge had no effect as long as 28 days later, at which time NAc CREB phosphorylation had normalized. Overexpression of dominant negative mutant CREB prevented PPI recovery induced by chronic quinpirole treatment. Chronic quinpirole or ropinirole treatment produces sustained PPI recovery; CREB activity in the NAc is required to induce PPI recovery but not to maintain it. The results suggest that transcriptional regulation by CREB mediates long-lasting changes occurring within NAc circuits to promote recovery of sensorimotor gating.

Properties of cannabinoid-dependent long-term depression in the leech

Previously, a cannabinoid-dependent form of long-term depression (LTD) was discovered at the polysynaptic connection between the touch mechanosensory neuron and the S interneuron (Li and Burrell in J Comp Physiol A 195:831-841, 2009). In the present study, the physiological properties of this cannabinoid-dependent LTD were examined. Increases in intracellular calcium in the S interneuron are necessary for this form of LTD in this circuit. Calcium signals contributing to cannabinoid-dependent LTD are mediated by voltage-dependent calcium channel and release of calcium from intracellular stores. Inositol triphosphate receptors, but not ryanodine receptors, appear to mediate this store-released calcium signal. Cannabinoid-dependent LTD also requires activation of metabotropic serotonin receptors, possibly a serotonin type 2-like receptor. Finally, this form of LTD involves the stimulation of nitric oxide synthase and a decrease in cyclic adenosine monophosphate signaling, both of which appeared to be downstream of cannabinoid receptor activation. Based on these findings, the cellular signaling mechanisms of cannabinoid-dependent LTD in the leech are remarkably similar to vertebrate forms of cannabinoid-dependent synaptic plasticity.

Novel imidazoline compounds as partial or full agonists of D 2-like dopamine receptors inspired by I 2-imidazoline binding sites ligand 2-BFI

Based on the well known biological versatility of the imidazoline nucleus, we prepared the novel derivatives 3a– k inspired by 2-BFI scaffold to assess imidazoline molecules as D 2-like dopamine receptor ligands. Conservative chemical modifications of the lead structure, such as the introduction of an hydroxy group in the aromatic ring alone or associated with N-benzyl substitution, provided partial ( 3f) or nearly full ( 3e and 3h) agonists, all endowed with D 2-like potency comparable to that of dopamine.

Serotonin has kinin-like activity in stimulating secretion by Malpighian tubules of the house cricket Acheta domesticus

Serotonin stimulates secretion by Malpighian tubules (MT) of a number of insects, and functions as a diuretic hormone in Rhodnius prolixus and in larval Aedes aegypti. Serotonin is here shown to be a potent stimulant of secretion by MT of the house cricket, Acheta domesticus, with an apparent EC 50 of 9.4 nmol L −1, although its diuretic activity is just 25% of the maximum achievable with either the native CRF-related peptide, Achdo-DH, or a crude extract of the corpora cardiaca. In this respect, the diuretic activity of serotonin is similar to that of the cricket kinin Achdo-KI, and when tested together their actions are not additive, which suggests they target the same transport process. Consistent with this suggestion, the activity of serotonin is chloride-dependent and is associated with a non-selective stimulation of NaCl and KCl transport. In common with Achdo-KI, serotonin has no effect on cAMP production by isolated MT, and both act synergistically with exogenous 8bromo-cAMP in stimulating fluid secretion, most likely by promoting the release of Ca 2+ from intracellular stores. A number of serotonin agonists and antagonists were tested to determine the pharmacological profile of receptors on cricket MT. The results are consistent with the diuretic activity of serotonin being mediated through a 5-HT 2-like receptor.

Central angiotensin II stimulates cutaneous water intake behavior via an angiotensin II type-1 receptor pathway in the Japanese tree frog Hyla japonica

Angiotensin II (Ang II) stimulates oral water intake by causing thirst in all terrestrial vertebrates except anurans. Anuran amphibians do not drink orally but absorb water osmotically through ventral skin. In this study, we examined the role of Ang II on the regulation of water-absorption behavior in the Japanese tree frog ( Hyla japonica). In fully hydrated frogs, intracerebroventricular (ICV) and intralymphatic sac (ILS) injection of Ang II significantly extended the residence time of water in a dose-dependent manner. Ang II-dependent water uptake was inhibited by ICV pretreatment with an angiotensin II type-1 (AT 1) receptor antagonist but not a type-2 (AT 2) receptor antagonist. These results suggest that Ang II stimulates water-absorption behavior in the tree frog via an AT 1-like but not AT 2-like receptor. We then cloned and characterized cDNA of the tree frog AT 1 receptor from the brain. The tree frog AT 1 receptor cDNA encodes a 361 amino acid residue protein, which is 87% identical to the toad ( Bufo marinus) AT 1 receptor and exhibits the functional characteristics of an Ang II receptor. AT 1 receptor mRNAs were found to be present in a number of tissues including brain (especially in the diencephalon), lung, large intestine, kidney and ventral pelvic skin. When tree frogs were exposed to dehydrating conditions, AT 1 receptor mRNA significantly increased in the diencephalon and the rhombencephalon. These data suggest that central Ang II may control water intake behavior via an AT 1 receptor on the diencephalon and rhombencephalon in anuran amphibians and may have implications for water consumption in vertebrates.

Dopamine down-regulates activity of alkaline phosphatase in Drosophila: The role of D2-like receptors

The effect of a rise in dopamine (DA) level as a result of a mutation, stress or pharmacological treatment on the activity of the enzyme of its synthesis, alkaline phosphatase (ALP) in females of Drosophila virilis and Drosophila melanogaster has been studied. It has been found that regardless of its nature, a rise in DA level has a negative effect on ALP activity, which indicates that DA down-regulates activity of the enzyme. The effects of bromocriptine (an agonist of Drosophila dopamine 2-like receptor (DD2R)) on ALP activity have been studied. ALP activity was found to drop in response to bromocriptine in flies. Conversely ALP activity was increased in flies with reduced DD2R expression (i.e. Actin5C-Gal4 > UAS-ds-DD2R RNA-interference flies) vs. corresponding controls (i.e. Actin5C-Gal4 > w1118 flies). Bromocriptine treatment of RNAi flies rescues ALP activity to the level typical of Actin5C-Gal4 > w1118 flies. A change in DD2R number or availability was found not to prevent the response of ALP to heat stress, but to change the intensity of its response to the stress exposure. The role of D2-like receptors in down-regulation of ALP activity by DA and in ALP response to stressor in Drosophila is discussed.

Microinjection of neuropeptide S into the rat ventral tegmental area induces hyperactivity and increases extracellular levels of dopamine metabolites in the nucleus accumbens shell

The newly identified neuropeptide S (NPS) is mainly expressed in a group of neurons located between the locus coeruleus and Barrington's nucleus in the brainstem. Central administration of NPS increases motor activity and wakefulness, and it decreases anxiety-like behavior and feeding. The NPS receptor (NPSR) is widely distributed in various brain regions including the ventral tegmental area (VTA). The mesolimbic dopaminergic system originates in the VTA, and activation of the system produces hypermotor activity. Therefore, we hypothesized that NPS-induced hypermotor activity might be mediated by activation of the mesolimbic dopaminergic pathway via the NPSR expressed in the VTA. Intra-VTA injection of NPS significantly and dose-dependently increased horizontal and vertical motor activity in rats, and the hyperactivity was significantly and dose-dependently inhibited by pre-administration of sulpiride, a DA D 2-like receptor antagonist, into the shell of the nucleus accumbens (NAcSh). Intra-VTA injection of NPS also significantly increased extracellular 3,4-dihydroxy-phenyl acetic acid and homovanillic acid levels in the NAcSh of freely moving rats. These results support the idea that NPS activates the mesolimbic dopaminergic system presumably via the NPSR located in the VTA, thereby stimulating motor activity.

Different striatal D 2-like receptor function in an early stage after unilateral striatal lesion and medial forebrain bundle lesion in rats

Unilateral striatal lesion and complete medial forebrain bundle (MFB) lesion by 6-hydroxydopamine in rats have been widely used as Parkinson disease (PD) models. However, the difference of pre- and post-synaptic dopamine (DA) system in these two models are not well concerned. In order to investigate the pathophysiologic difference between the MFB lesion rats and striatal lesion rats, we studied the variation of pre-synaptic DA transporter and post-synaptic D 2-like receptor in nigrostriatal DA system using binding assay, behavioral test and a small animal PET. Our data showed that there was a same tendency of the striatal DA transporter decrease both in MFB lesion rats and striatal lesion rats 4 weeks after lesion, however, it showed increase (up-regulation) of D 2-like receptor in the MFB lesion rats, whereas showed decrease (down-regulation) in the striatal lesion rat. This finding strongly indicated the different dynamic pathophysiologic process between the MFB lesion model and striatal lesion model. MFB lesion model mimics an early stage of PD, whereas striatal lesion model mimics Parkinson syndrome, such as vascular Parkinson syndrome. Such difference should be taken into account in the selection of these model systems.

Remote functionalization of SCH 39166: Discovery of potent and selective benzazepine dopamine D 1 receptor antagonists

A series of novel benzazepine derived dopamine D 1 antagonists have been discovered. These compounds are highly potent at D 1 and showed excellent selectivity over D 2 and D 4 receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D 1 and good selectivity over D 2-like receptors.

A tryptamine-derived catecholaminergic enhancer, (−)-1-(benzofuran-2-yl)-2-propylaminopentane [(−)-BPAP], attenuates reinstatement of methamphetamine-seeking behavior in rats

Relapse to drug craving is problematic in treatment for drug abuse. Evidence suggests inactivation of dopaminergic neurotransmission during drug withdrawal. Meanwhile, a tryptamine analogue, (−)-1-(benzofuran-2-yl)-2-propylaminopentane [(−)-BPAP], has been reported to enhance electrical stimulation of monoamine release. This study examined the effect of (−)-BPAP on reinstatement of methamphetamine-seeking behavior in an animal model of relapse to drug abuse. Rats were trained to i.v. self-administer methamphetamine paired with a light and tone (methamphetamine-associated cues) under a fixed-ratio 1 schedule of reinforcement for 10 days. After extinction session under saline infusions without cues, a reinstatement test under saline infusions was begun. Reinstatement induced by methamphetamine-associated cues or methamphetamine-priming injections was attenuated by repeated administration of (−)-BPAP during the extinction phase. Acute administration of (−)-BPAP on test day dose-dependently attenuated both reinstatements. Acute administration of (−)-BPAP neither reinstated methamphetamine-seeking behavior alone nor affected methamphetamine self-administration. Pretreatment with either R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH-23390), a dopamine D 1-like receptor antagonist, or amisulpride, a dopamine D 2-like receptor antagonist, did not appreciably affected the acute effect of (−)-BPAP on both reinstatements. Co-pretreatment with the dopamine receptor antagonists failed to alter the effects of (−)-BPAP. Meanwhile, pretreatment with a dopamine D 1-like receptor agonist, (+/−)-6-chloro-7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrobromide (SKF-81297), dose-dependently attenuated reinstatement induced by the cues or methamphetamine-priming injections. In contrast to (−)-BPAP, pretreatment with SCH-23390 reversed the effects of SKF-81297. Our findings suggest activation of dopamine D 1-like receptors results in attenuation of the reinstatement of methamphetamine-seeking behavior. Additionally, our findings provide evidence to develop (−)-BPAP and dopamine D 1-like receptor agonists as an anti-relapse medication for methamphetamine abusers.

MT 2-like melatonin receptor modulates amplitude receptor potential in visual cells of crayfish during a 24-hour cycle

Retinular photoreceptors are structures involved in the expression and synchronization of the circadian rhythm of sensitivity to light in crayfish. To determine whether melatonin possesses a differential effect upon the receptor potential (RP) amplitude of retinular photoreceptors circadian time (CT)-dependent, we conducted experiments by means of applying melatonin every 2 h during a 24-hour cycle. Melatonin with 100 nM increased RP amplitude during subjective day to a greater degree than during subjective night. To determine whether MT 2 melatonin receptors regulate the melatonin-produced effect, we carried out two experiments, circadian times (CTs) 6 and 18, which included the following: (1) application of the MT 2 receptor selective agonist 8-M-PDOT and antagonist DH97, and (2) the specific binding of [ 125I]-melatonin in eyestalk membranes. The amount of 10 nM of 8-M-PDOT increased RP amplitude in a similar manner to melatonin, and 1 nM DH97 abolished the increase produced by melatonin and 8-M-PDOT. Binding of [ 125I]-melatonin was saturable and specific. Scatchard analysis revealed an affinity constant ( K d) of 1.1 nM and a total number of binding sites ( B max) of 6 fmol/mg protein at CT 6, and a K d of 1.46 nM and B max of 7 fmol/mg protein at CT 18. Our results indicate that melatonin increased RP amplitude of crayfish retinular photoreceptors through MT 2-like melatonin receptors. These data support the idea that melatonin is a signal of darkness for the circadian system in crayfish retinular cells.

Structure–activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives

Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D 1-like and/or D 2-like dopamine receptors in striatal membranes, although they were unable to inhibit [ 3H]-dopamine uptake in striatal synaptosomes. The halogen placed on the benzylic ring in 1-benzyl-THIQs, compounds of the series 1, 2′-bromobenzyl derivatives with K i values into the nanomolar range, and the series 2, 2′,4′-dichlorobenzyl-THIQ homologues, proves to be an important factor to modulate affinity at dopamine receptor.

3H]-YM-09151-2 binding sites in human brain postmortem

The controversial and limited data on the distribution of dopamine (DA) receptors of type 4 (D 4) in the human brain prompted us to explore their density and pharmacological characteristics in the prefrontal cortex, striatum and hippocampus, through a series of binding assays. Brain samples were taken during autopsy from seven subjects. Tissue homogenates were incubated with increasing concentration of [ 3H]-YM-09151-2, a D 2-like receptor antagonist, and L-745,870 and/or sulpiride to define the non-specific binding, while PPAP was used to block sigma receptors. The results showed a low density of D 4 receptors in the hippocampus only, with a preponderance of D 2/D 3 and sigma receptors in the prefrontal cortex and striatum. In conclusion, these findings underline that it is possible to label D 4 receptors by means of [ 3H]-YM-09151-2, provided that D 2, D 3 and sigma receptors are blocked.

Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice

Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D 1-like and/or D 2-like dopamine receptors in striatal membranes, and were unable to inhibit [ 3H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D 1 or D 2 affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure–activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline ( 1e) with the highest affinity towards D 2-like receptors ( K i value of 66 nM) and the highest selectivity (49-fold D 2 vs D 1) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04–25 mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01 mg/kg) that did not modify locomotor activity. The haloperidol (0.03 mg/kg), a D 2 receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.

F15063, a potential antipsychotic with dopamine D 2/D 3 receptor antagonist, 5-HT 1A receptor agonist and dopamine D 4 receptor partial agonist properties: Influence on neuronal firing and neurotransmitter release

F15063 ( N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-(3-cyclopenten-1-yl-benzyl)-amine) is a potential antipsychotic with dopamine D 2/D 3 receptor antagonist, 5-HT 1A receptor agonist and dopamine D 4 receptor partial agonist properties. Herein, we compared its effects on rat ventral tegmental area dopamine and dorsal raphe serotonin electrical activity with those of the dopamine D 2 receptor partial agonist/5-HT 1A receptor agonist, SSR181507. Further, we investigated the modulation of extracellular dopamine and noradrenaline in the medial prefrontal cortex and serotonin in the hippocampus of freely moving rats by F15063 using in vivo microdialysis. In the ventral tegmental area, F15063 (200–700 µg/kg, i.v.) did not alter the electrical activity of dopamine neurons whereas SSR181507 (250–1000 µg/kg, i.v.) partially inhibited it, consistent with dopamine D 2 receptor partial agonism. Both compounds reduced the inhibition of firing rate induced by the full agonist apomorphine. In the dorsal raphe, both ligands suppressed firing activity, consistent with agonism at 5-HT 1A autoreceptors, although SSR181507 (25–75 µg/kg, i.v.) was more potent than F15063 (100–300 µg/kg, i.v.). F15063 (0.63–40 mg/kg, i.p.) dose-dependently increased dopamine levels in the prefrontal cortex and decreased hippocampal 5-HT. These effects were reversed by the selective 5-HT 1A receptor antagonist WAY100635 (0.16 mg/kg, s.c.), indicating that they were mediated by 5-HT 1A receptors (at post- and pre-synaptic levels, respectively). In the medial prefrontal cortex, noradrenaline levels were moderately but significantly increased by F15063 at 2.5 mg/kg. In conclusion, whereas SSR181507 exhibits (partial) agonism at dopamine D 2 and 5-HT 1A receptors, F15063 blocks dopamine D 2-like receptors whilst activating 5-HT 1A receptors. Such a profile distinguishes F15063 from SSR181507 and currently available antipsychotic drugs.

Synthesis and evaluation of ligands for D 2-like receptors: The role of common pharmacophoric groups

Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D 2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 4′-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D 2-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors.