Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Butaclamol”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed1998

Functional analysis of the D2L dopamine receptor expressed in a cAMP-responsive luciferase reporter cell line.

A Chinese hamster ovary (CHO) cell line expressing the firefly luciferase gene under the control of six cAMP response elements (CREs) was stably transfected with the long form of the rat D2 dopamine receptor. Saturation binding analysis using [3H]spiperone showed that the receptor was expressed at low levels (Bmax = 96.5+/-15.8 fmol/mg), but with an affinity characteristic of the D2 receptor (Kd = 21.5+/-3.7 pM). Luciferase expression in this cell line was modified in a dose dependent manner with dopamine receptor agonists (N-propylapomorphine > apomorphine > quinpirole > dopamine) and antagonists (spiperone > (+)-butaclamol > D0710 > (-)-sulpiride > tiapride > remoxipride), according to their rank order of potency in binding and cAMP accumulation studies. Dopamine-mediated inhibition of forskolin-stimulated luciferase expression was pertussis toxin sensitive. This demonstrated the efficiency of the luciferase reporter gene assay for the functional testing of D2 dopamine receptors, which are negatively coupled to the adenylyl cyclase signaling pathway, when heterogously expressed at low levels in CHO cells.

Adenylate Cyclase Toxin↗
PubMed1998

Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.

Animals↗
PubMed1999

Partial agonism at serotonin 5-HT1B and dopamine D2L receptors using a luciferase reporter gene assay.

We have used a luciferase reporter gene assay to study the functional responses of two G-protein-coupled receptors in Chinese hamster ovary (CHO) cells. The rank order of potency of drugs for the endogenous 5-HT1B receptor was 5-Hydroxytryptamine (5-HT) > zolmitriptan > dihydroergocristine > (-)lisuride (with no response to bromocriptine). However, only 5-HT and (-)lisuride produced a full functional response, with zolmitriptan and dihydroergocristine achieving 69+/-2% and 50+/-1% of the maximal response. In the same cells stably transfected with the rat dopamine D2L receptor, dopamine and bromocriptine produced a full agonist functional response, whilst (-)lisuride produced a biphasic response curve, indicating activity at both the endogenous 5-HT1B and exogenous dopamine D2L receptors. Using the receptor specific antagonists, pindolol and (+)butaclamol, (-)lisuride was shown to produce 52% of the maximal response at the dopamine D2 receptor relative to dopamine. In comparison to a cAMP accumulation assay, the rank orders of potency and intrinsic activity were the same for all compounds used. These results demonstrate that this reporter gene assay is capable of discriminating both potency and efficacy of drugs and can be used to characterise partial agonists at endogenously and heterologously expressed receptors in CHO cells.

Animals↗
PubMed1998

Pharmacological evaluation of [11C]A-84543: an enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors.

[11C]A-84543, 3-[(1-[11C]methyl-2(S)-pyrrolidinyl)methoxy]pyridine, is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer in mice showed high brain uptake and a distribution consistent with the density of nAChRs. Highest uptake was observed in the thalamus (9.6 %ID/g), cortex (9.9 %ID/g), superior colliculus (7.6 %ID/g) and hippocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of specificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 30 min post-injection. Radioactivity in the thalamus and superior colliculus was reduced by 33% by pre-administration of unlabeled A-84543. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [11C]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively, while lobeline, which also interacts with central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [11C]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[(1-[11C]methyl-2(R)-pyrrolidinyl)methoxy] pyridine, high brain uptake was also observed, but with a low thalamus/cerebellar ratio of 1.4 at 30 min post-injection. [11C]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation as a possible PET radiotracer.

Animals↗
PubMed1997

Effects of chronic ethanol treatment and ethanol withdrawal on [3H]SCH23390 binding to rat striatal membranes.

The effects of chronic ethanol administration and ethanol withdrawal on the kinetic and pharmacological properties of [3H]SCH23390 binding sites and the labelling of central dopamine D-1 receptors were studied in the striatum of the rat. Chronic 40 day ethanol treatment produced a statistically significant decrease (p < 0.05) in maximum binding (Bmax) on striatal dopamine D-1 receptors of the rat, KD remaining unaltered. The withdrawal of ethanol did not affect the kinetic binding parameters. The rank order of potency in displacing the specific [3H]SCH23390 binding of several dopamine antagonists, agonists and serotonin-related drugs was consistent with the pharmacological profile of dopamine D-1 receptors. Chronic ethanol treatment led to a statistically significant increase in receptor affinity (lower Ki than controls) for (+)-butaclamol (p < 0.05). Ethanol withdrawal for 24 hr increased the affinity of [3H]SCH23390-labeled binding sites for norepinephrine. The addition of 0.03-0.68 M ethanol in vitro had no significant effects on [3H]SCH23390 binding in striatal preparations taken from both control and ethanol-treated rats. The results show that rat striatal [3H]SCH23390-labelled binding sites are affected by different conditions of ethanol exposure, possibly suggesting the medication of striatal dopamine pathways in the responses to ethanol intoxication.

Animals↗
PubMed1998

Discriminative stimulus properties of the putative dopamine D3 receptor agonist, (+)-PD 128907: role of presynaptic dopamine D2 autoreceptors.

The putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 microg kg(-1), s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (-) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (+/-)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent alpha-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists > 40 and > 100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.

Animals↗
PubMed1999

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.

Adrenergic Antagonists↗
PubMed1999

Actions of butyrophenones and other antipsychotic agents at NMDA receptors: relationship with clinical effects and structural considerations.

Haloperidol inhibits NMDA receptors with higher affinity for NMDA receptors composed of NR1/2B compared with NR1/2A. To assess whether the clinical effects of haloperidol and other antipsychotic agents are mediated through this site on NMDA receptors and to examine structure activity relationships at this site, we examined the ability of a variety of drugs with neuroleptic actions to inhibit NMDA receptor function. Many antipsychotic agents inhibit 125I-MK 801 binding to the NMDA receptor with IC50 values in the micromolar range. The rank order of potency for inhibition of binding to adult rat forebrain was trifluperidol (TFP) > clozapine = fluphenazine = reduced haloperidol = spiperone = trifluoperazine = butaclamol >> pimozide = risperidone = sulpiride. These findings match the molecular biological specificity of the agents, with trifluperidol having a marked preference for NR1/2B (epsilon2) receptors. Mutations at epsilon2E201, which alter the effects of haloperidol, also decrease the affinity of TFP but not other modulators, showing that the effect of TFP but not other modulators is mediated by this residue of the NMDA receptor. The present results demonstrate that while TFP acts on NMDA receptors in a manner similar to haloperidol, other antipsychotic agents do not share the specific pharmacological properties of this action, suggesting that their clinical mechanism is not mediated by this receptor.

Animals↗
PubMed2001

Sensitization of adenylate cyclase induced by a dopamine D2 receptor mutant: inverse agonism by D2 receptor antagonists.

Mutations of residues in the third intracellular loops of several G-protein coupled receptors have been shown to confer constitutive activation. The authors investigated the effects of one such mutation in the dopamine D2 receptor. Compared to the wild type D2, the mutant D2 receptor (D2T344K) showed a substantial increase in agonist affinity with affinity for antagonists unchanged. The increased agonist affinity was unaffected by pertussis toxin treatment, indicating it is an intrinsic property of the mutant receptor. The potency of dopamine for acute inhibition of forskolin-stimulated cAMP production in stably expressing Chinese Hamster Ovary (CHO) cells was higher for the mutant than the wild type receptor. CHO cells stably expressing D2T344K displayed enhanced responses to forskolin-stimulated adenylate cyclase activity compared with cells stably expressing the wild type D2 receptor. The increased forskolin responsiveness of adenylate cyclase is similar to the sensitization previously observed with wild type D2 receptor after agonist treatment. Adenylate cyclase responsiveness of CHO cells stably expressing D2T344K receptor was not further increased by agonist treatment. Sensitization was blocked by pertussis toxin and D2 receptor antagonists haloperidol, butaclamol, and clozapine, indicating inverse agonist activity of these compounds at D2T344K. Inverse agonist activity was further demonstrated by the finding that overnight treatment with these compounds drastically increased the density of the mutant receptor but had minimal effect on the density of the wild type receptor. Taken together, these results suggest the authors have generated a constitutively active dopamine D2 receptor capable of sensitizing adenylate cyclase in the absence of agonist activation.

Adenylyl Cyclase Inhibitors↗
PubMed1997

Further studies on the suppression of luteinizing hormone release due to activation of medial preoptic-anterior hypothalamic area mu-opioid receptors.

Our laboratory has previously demonstrated that specific activation of mu-opioid receptors in the medial preoptic-anterior hypothalamic area with [D-Ala2, N Me-Phe4, Gly-ol5]-enkephalin (DAGO) suppresses luteinizing hormone secretion in the ovariectomized rat [29]. In the present study, three experiments were undertaken to ascertain whether changes in the activity of norepinephrine or dopamine neurons modulate the decrease in luteinizing hormone release in response to DAGO. The first experiment utilized push-pull perfusion in conjunction with HPLC to assess in vivo norepinephrine release in the medial preoptic-anterior hypothalamic area in response to perfusion of this site with DAGO (5 micrograms/h). DAGO significantly decreased luteinizing hormone release, but perfusate norepinephrine levels did not change. In the second experiment, push-pull perfusion in the medial preoptic-anterior hypothalamic area with cerebrospinal fluid (CSF) or CSF containing DAGO was done in rats pretreated with the norepinephrine synthesis inhibitor, FLA-63. This drug pretreatment had no effect on the DAGO-induced suppression of luteinizing hormone secretion. In experiment 3, push-pull perfusion in the medial preoptic-anterior hypothalamic area with CSF followed by CSF containing DAGO was done in rats pretreated with vehicle, or a dopamine receptor antagonist, either pimozide or d-butaclamol. Neither dopamine receptor antagonist had any effect on the DAGO-induced suppression of luteinizing hormone release. Thus, these studies do not support a role for alterations in the activity of norepinephrine or dopamine neurons in mediating the suppression of luteinizing hormone release in response to activation of mu-opioid receptors in the medial preoptic-anterior hypothalamic area in the ovariectomized rat.

Animals↗
PubMed1997

[3H]nemonapride binding in human caudate and putamen.

The binding of [3H]nemonapride to human postmortem caudate and putamen tissue was autoradiographically investigated using several antipsychotic drugs. Saturation experiments revealed a single population of binding sites (dissociation constant (KD) 0.38 +/- 0.01 nM, and total binding capacity (BMAX) 55 fmol/TE). Prototypic dopamine (DA) receptors antagonists displaced [3H]nemonapride in a monophasic manner. The order of displacement potency was expected for DA D2-like receptors: spiperone > (+)butaclamol > or = chlorpromazine > (-)sulpiride > ketanserin. Displacement with serotonergic antagonists suggests that in human caudate and putamen tissue [3H]nemonapride may have a very low affinity serotonergic component. However, [3H]nemonapride displays a high affinity and selectivity for DA D2-like receptors and should make, it a preferred compound for tritium-based autoradiography.

Adolescent↗
PubMed2000

Chiral analysis of selected dopamine receptor antagonists in serum using capillary electrophoresis with cyclodextrin additives.

Dopamine D-2 receptor antagonists' eticlopride and sulpiride were determined in serum using capillary electrophoresis with cyclodextrin additives. Chiral resolution of S(-) and R(+) sulpiride and eticlopride were achieved using 2% sulfated-beta-cyclodextrin (S-beta-CD) in 20 mM citrate run buffer (pH 2.90). A 72-cm fused silica capillary operated in the reversed polarity mode voltage of 20 kV was used for the analysis. The analytes of interest were isolated from serum using a solid phase extraction procedure with recoveries in excess of 85% for all four enantiomers. The D-2 receptor antagonist (-) butaclamol was used as internal standard. The limits of detection were 0.3 and 0.1 microg/ml for S(-) and R(+) eticlopride and for S(-) and R(+) sulpiride, respectively, in 1 ml of serum. The limits of quantitation were 2 and 1 microg/ml for S(-) and R(+) eticlopride, and for S(-) and R(+) sulpiride, respectively. Calibration curves were linear over the 2-20 micro/ml range for eticlopride and 1-20 microg/ml range for sulpiride. The coefficients of determination were greater than 0.99 (n = 12 for eticlopride and n = 15 for sulpiride). Precision and accuracy of the method were 0.27-6.38 and 0.20-3.60% for S(-) eticlopride, 2.33-4.28 and 0.80-5.73%, for R(+) eticlopride, 3.46-6.84 and 0.80-4.26%, for S(-) sulpiride; and 4.71 -6.47 and 2.00-6.67%, for R(+)-sulpiride, respectively.

Buffers↗
PubMed1998

Binding of [3H]PD 128907, a putatively selective ligand for the D3 dopamine receptor, in rat brain: a receptor binding and quantitative autoradiographic study.

[3H]PD 128907 has been proposed as a selective ligand for the D3 dopamine receptor. This study characterizes the binding of this radioligand in rat brain using in vitro radioligand binding and autoradiographic methods. In radioligand binding studies, [3H]PD 128907 exhibited 0.3 nmol/L affinity for a single, low density site in ventral striatal membranes. The pharmacological profile for [3H]PD 128907 was similar to that of [3H](+)-7-OH-DPAT with the rank order of potency for dopamine agonists being PD 128907 approximately 7-OH-DPAT approximately quinpirole > or = dopamine; for antagonists, spiperone > (+)-butaclamol approximately domperidone > or = haloperidol > SCH 23390. Guanyl nucleotides had no effect on the binding of either ligand. These observations indicate labeling of a dopaminergic site with characteristics consistent with the D3 receptor. In autoradiographic studies, highest densities of [3H]PD 128907-labeled sites were observed in islands of Calleja followed by the nucleus accumbens, nucleus of the horizontal limb of the diagonal band, the molecular layer of cerebellar lobule X, and the ventral caudate/putamen.

Animals↗
PubMed1999

In vivo binding of [11C]nemonapride to sigma receptors in the cortex and cerebellum.

Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D2-like receptor ligand in pharmacological and neurological studies, and 11C-labeled analog ([11C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [11C]NEM binds in vivo to sigma receptors. [11C]NEM and one of six dopamine D2-like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [11C]NEM was measured by a tissue dissection method. The striatal uptake of [11C]NEM was reduced by D2-like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D4 receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D2-like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [11C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [11C]NEM binds in vivo not only to dopamine D2-like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum.

Animals↗
PubMed1991

Synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro- 1H-3- benzazepine (TISCH): a high affinity and selective iodinated ligand for CNS D1 dopamine receptor.

The synthesis and resolution of (+-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1 H-3- benzazepine, (+/-)-TISCH (8) has been achieved by resolution of intermediate 4, the O-methoxyl, 3'-bromo derivative, as the diastereomeric camphor sulfonate salt. The final products, R-(+)-8 and S-(-)-8, were prepared by treatment of R-(+)- or S-(-)-7, the 3'-tributyltin intermediates, with iodine in chloroform, followed by O-demethylation. By using HPLC with a chiral column, the optical purity (greater than 99%) of the intermediates and the final compounds was determined. Radioiodination was achieved by an iodo-destannylation reaction with sodium [125I]iodide and hydrogen peroxide. As expected, the R-(+)-[125I]-8 (the active isomer) displayed high affinity and selectivity to the CNS D-1 receptor in rat striatum tissue preparation (Kd = 0.205 nM). The rank order of potency was as follows: SCH-23390 (1a) greater than (+/-)-8 greater than (+)-butaclamol greater than spiperone, WB4101 greater than dopamine, 5-HT. After an iv injection, the R-(+)-[125I]-8 penetrated the blood-brain barrier with ease and displayed specific regional distribution corresponding to the D-1 receptor density, while the S-(-)-[125I]-8 showed no specific uptake. The data suggest that the ligand may be useful as a pharmacological tool for characterizing the D-1 dopamine receptor. When labeled with I-123, this ligand is a potential agent for in vivo imaging of CNS D-1 dopamine receptor.

Animals↗
PubMed1990

Synthesis and characterization of iodobenzamide analogues: potential D-2 dopamine receptor imaging agents.

(S)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6- methoxybenzamide ([123I]IBZM) is a central nervous system (CNS) D-2 dopamine receptor imaging agent. In order to investigate the versatility of this parent structure in specific dopamine receptor localization and the potential for developing new dopamine receptor imaging agents, a series of new iodinated benzamides with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was synthesized and radiolabeled, and the in vivo and in vitro biological properties were characterized. The best analogue of IBZM is IBF (21). The specific binding of [125I]IBF (21) with rat striatal tissue preparation was found to be saturable and displayed a Kd of 0.106 +/- 0.015 nM. Competition data of various receptor ligands for [125I]IBF (21) binding show the following rank order of potency: spiperone greater than IBF (21) greater than IBZM greater than (+)-butaclamol greater than (+/-)-ADTN,6,7 greater than ketanserin greater than SCH-23390 much greater than propranolol. The in vivo biodistribution results confirm that [125I]IBF (21) concentrated in the striatal area after iv injection into rats. The study demonstrates that [123I]IBF (21) is a potential agent for imaging CNS D-2 dopamine receptors.

Animals↗
PubMed1988

Dopamine D-2 receptor imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N- [(1-ethyl-2-pyrrolidinyl)methyl]benzamide.

In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-[125I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamide, [125I]IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-[125I]IBZM showed high specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone greater than (S)-(-)-IBZM greater than (+)-butaclamol much greater than (R)-(+)-IBZM greater than (S)-(-)-BZM greater than dopamine greater than ketanserin greater than SCH23390 much greater than propanolol. The results indicate that [125I]IBZM binds specifically to the dopamine D-2-receptor with stereospecificity. The [123I]IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.

Animals↗
PubMed2000

Atypical SCH23390 binding sites are present on bovine adrenal medullary membranes.

D1-selective dopamine receptor agonists inhibit secretagogue-stimulated catecholamine secretion from bovine adrenal chromaffin cells. The purpose of the studies reported here was to use the radiolabeled D1-selective dopamine receptor antagonist, SCH23390, to characterize putative D1-like dopamine receptors responsible for this effect. Characterization of SCH23390 binding sites demonstrated an unusual pharmacological profile inconsistent with classical D1-like receptors. [125I]SCH23390 bound to adrenal medullary membranes was competed for by nonradioactive iodo-SCH23390 (Kd = 490 +/- 50 nM), but not by (+)butaclamol. Other classical D1 antagonists had little, if any, effect. Competition with dopamine receptor agonists demonstrated a relative rank order of potency profile characteristic of D1-like dopamine receptors, however, K(i)s were higher than those found in other tissues. The K(i)s for competition of [125I]SCH23390 binding by Cl-APB and SKF38393 (16 and 118 microM, respectively) are nearly identical to the IC(50)s previously observed for inhibition of secretion (9 and 100 microM, respectively). Combined these data suggest that adrenal medullary membranes contain a novel SCH23390 binding site involved in the inhibition of secretion by D1-selective agonists.

Adrenal Medulla↗