DOCSLIB.ORG

High Affinity Dopamine D2 Receptor Radioligands. 1. Regional Rat Brain Distribution of Iodinated Benzamides

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
High Affinity Dopamine D2 Receptor Radioligands. 1. Regional Rat Brain Distribution of Iodinated Benzamides High Affinity Dopamine D2 Receptor Radioligands. 1. Regional Rat Brain Distribution of Iodinated Benzamides Robert M. Kessler, M. Sib Ansari, Tomas de Paulis, Dennis E. Schmidt, Jeffrey A. Ctanton, Howard E. Smith, Ronald G. Manning, David Gillespie, and Michael H. Ebert Departments of Radiology, Chemistry, and Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee a substituted benzamide. Spiperone and its derivatives, Five 12Sl-labeled substituted benzamides, which are close e.g., [~ ~C]-N-methylspiperone, have very high affinities for structural analogues of (S)-sulpiride, eticlopride, and isore- the D2 receptor but also are potent serotonergic ligands moxipride, were evaluated for their selective in vivo uptake and have nonreversible binding in vivo (7-10). The sub- into dopamine D2 receptor rich tissue of the rat brain. "lodo- stituted benzamides used in man. [~]C]raclopride (11,12) pride" (Ko 0.88 nM), an iodine substituted benzamide struc- and [~23I]IBZM (13,14), are selective for the D2 receptor, turally related to sulpiride, displayed a maximal stria- have reversible binding in vivo, and have moderate affinity tum:cerebellar uptake ratio of 7.6. Demonstration of satura- for the D2 receptor. Both Seeman (15) and Ross (•6) have tion of the receptor with [12Sl]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar recently demonstrated that [3H]raclopride binding in vivo uptake, to define nonspecific binding. Two other ligands struc- is inhibited by endogenous free synaptic dopamine, while turally related to eticlopride, "iclopride" (KD 0.23 riM) and binding of a high affinity ligand to the D2 receptor was "itopride" (Ko 0.16 nM), displayed maximal striatal:cerebellar not significantly inhibited by dopamine (15). Thus, ligands uptake ratios of 9.8 and 3.3, respectively. The most potent with very high affinity may be needed for accurate in vivo ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 measurements of receptor number. nM) showed striatal:cerebellar uptake ratios of 234 and 65, A dopamine D2 ligand for single photon emission to- respectively. The observed uptake ratios correlated poorly mography (SPECT) imaging would ideally have great se- with the affinity constants for the dopamine D2 receptor alone, lectivity and high affinity for the D2 receptor, low nonspe- but were highly correlated (r = 0.92) with the product of the cific binding, and brain uptake adequate for imaging. The receptor dissociation constant (Ko) and the apparent lipophil- in vivo striatal:cerebellar ratios for [~C]raclopride and icity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, [J231]IBZM have been reported as 4:1 (11) and 2:1 (14), with maximal uptake occurring for ligands having log kw 2.4- respectively, in man; these ratios are sufficient for imaging 2.8. but not optimal. Many substituted benzamides are rela- tively selective for the D2 receptor (1 7); substituted benz- J Nucl Med 1991; 32:1593-1600 amides with high affinity for the D2 receptor such as etictopride (18) and isoremoxipride (19) have been syn- thesized. Kessler and colleagues have recently reported a series of iodinated benzamides with high affinity for the Cerebral dopaminergic neurotransmission has been ex- D2 receptor (20-22), which are structurally related to tensively studied and has been shown to be involved in sulpiride and to these high affinity benzamides. The pres- the pathogenesis of Parkinson's disease (1) and progressive ent study was undertaken to determine if these compounds supranuclear palsy (2). It has been implicated in the etiol- might be suitable as potential D2 ligands for SPECT and ogy of a number of other disorders including schizophrenia to evaluate the relationship of receptor affinity and lipo- (3), affective disorders (4) and tardive dyskinesia (5,6). philicity to the regional brain uptake of these tracers. The Because of the widespread interest in cerebral dopami- compounds evaluated include iodopride, iclopride, ioxi- nergic function and the availability of radiolabeled, high pride, and epidepride. A preliminary evaluation of ito- affinity dopaminergic ligands, in vivo studies of dopamine pride, a substituted benzamide structurally related to eti- D2 receptors in man have been performed utilizing emis- clopride, was also performed. The structures of these and sion tomography. The majority of these studies of D2 related compounds are shown in Figure I. receptors have utilized either a derivative of spiperone or METHODS Drugs Received Oct. 24, 1990; revision accepted Feb. 26, 1991. For reprints contact: Robert M. Kessler, MD, Department of Radiology, Iodopride, (S)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2- VUMC, Nashville, Tennessee 37232-2675. methoxybenzamide (21), IBZM (13,23), eticlopride (24), and Iodinated Benzamides • Kessler et al 1593 The IC~, for inhibition of [3H]spiperone binding to striatal homogenate was determined as follows. Prior to incubation, the assay tubes were placed on ice and the assay started by addition of 0.5 ml of the tissue homogenate to each tube containing [3H] spiperone (at a final concentration of 300 pM), 10 nM ketanserin, t % ~ , ,l~plttd~ t(~d~rptltlc 10 uM pargyline, and the displacing ligand at a final concentration H H of from 0.001 to 100,000 rot,/ with a final volume of 2 ml. CONHCH2-H~ Nonspecific binding was determined using a concentration of 10 uM spiperone. Each tube was removed from ice, vortexed for c,~/IL.~L c' c,., ,)k..CL, c, c~., C~Hs- ~ - I 3 sec, and incubated at 25"C for 50 min. Incubation was termi- cl~, t,,pr,ti; t~ h~prldc it~prltJt" nated by filtration through Whatman GF/B filters presoaked in 0.3% polyethylenimine, using a Brandel model M-24R cell har- vester. The filters were rinsed for 10 sec with ice-cold Tris HC1 CONHCHj?%~ C...... .H /--~ buffer, the filter placed in a 20-ml plastic scintillation vial and 10 ml of scintillation fluid was added. Liquid scintillation counting I --OCH~ was performed using a Beckman LS3801 counter; efficiency was I\ttr¢" [I i~ )k t t ,r i, I~ t'llhl~-[H ldt ii,~liIrltt~ typically 45%. The Kt~ for ligand binding to striatat homogenates was deter- FIGURE 1. Structures of new iodinated substituted benzam- mined as follows. If frozen, the tissue was thawed, homogenized ides and parent compounds. The parent compounds are shown at 100-fold dilution (w:v) in a Tris-HC1 buffer for t5 sec using a in the left column and the corresponding iodinated derivatives on Brinkman Polytron at half-maximum speed. The homogenate the right. was centrifuged at 4°C at 10.000 x g for 15 min, the supernatant discarded, the pellet resuspended in the initial volume of fresh buffer, and centrifuged a second time. The supernatant was again ioxipride, (S)-N-[( 1-ethyt-2-pyrrolidinyl)methyl]-3-iodo-5,6-di- discarded and the pellet resuspended in a Tris-HC1 buffer con- methoxysalicylamide (25) were prepared as described in the raining 50 mM Tris pH 7.4, 120 mM NaCI, 2 mM CaCI~, 1 rrL,~/ literature. Ictopride, (S)-5-chloro-N-[(t-ethyl-2-pyrrolidi- MgSO4, 1 mM NaEDTA, and 100 uM Na ascorbate at a final nyl)methyl]-3-iodo-6-methoxysalicylamide (20), itopride, (S)-3- dilution of 500 w:v. Incubation was performed in duplicate in a ethyl-N-I( I -ethyl-2-pyrrolidin yl)methyl]-5-iodo-6-methoxysali- total of 2.0 ml Tris-HC1-Na buffer containing 0.5 ml tissue and cylamide, and epidepride, (S)-N-[( t-ethyl-2-pyrrolidinyl)methyl] 20 ul radioactive ligand (final concentration 0.001 nM to 500 -5-iodo-2,3-dimethoxybenzamide (26), were prepared from the nM). The tissue was incubated for 45 min at 250C and the appropriate iodine substituted benzoic acid derivatives as de- binding assay terminated by filtration as described above. The scribed tbr the corresponding bromo analogues (27). Raclopride filter was placed in a gamma counting tube and gamma spectrom- (27) and IBF (28) were gifts from Dr. H. Hall (Astra) and Dr. H. etry performed using a Searle Analytic Inc model 1 t 85, with 86% F. Kung (University of Pennsylvania), respectively. efficiency. Nonspecific binding was determined by adding 10 uM sulpiride to the incubation mixture. Data analysis was performed Radiolabeling using the EBDA program. Preparation of [~2'l]iodobenzamides at high specific activity was achieved by iododestannylation of the corresponding tribu- tvltinbenzamide (iodopride, epidepride) (21,26) or by electro- In Vivo Studies philic iodination of the corresponding desiodobenzamide (ioxi- Groups of four 200-250 g male Harlan-Sprague-Dawley rats pride, iclopride, and itopride)(23,29). No-carrier-added sodium were injected with 25 or 30 uCi of ~-~5I labeled iodobenzamide via [':q]iodide (2000 Ci/mmol) was oxidized in situ by chloramine- tail vein. The animals were killed at 5, 20, 40, 80, 160, and when T in dilute hydrochloric acid. Its subsequent reaction with the necessary., 320, 640. and 1,280 min after injection. The brains appropriate substituted benzamide gave the [~2~I]iodobenzamide were rapidly removed, washed in iced saline, regional brain with radiochemical yields of 50-60% after purification by reverse- dissection was performed, and the cerebellum and striatum were phase liquid chromatography (Waters 10 cm × 8 mm NOVA weighed and counted using gamma spectrometr2y. Pak-CN, ethanol:100 mM phosphate buffer (30:70) at pH 7.0, To assess the effect of haloperidol, 2 mg/kg haloperidol was flow rate 1.5 mi/min, and ambient temperature). administered intraperitoneally 60 min prior to the tail vein ad- ministration of 25 or 30 uCi ~2~l-labeled iodobenzamide. Groups In Vitro Receptor Binding Studies of four rats were killed at 60 rain after [125I]iodopride or [125I] Mate Harlan Sprague Dawley rats (200-300 g) were sacrificed~ iciopride injection, or 80 min after injection of [l-~-~I]epidepride the brain removed, dissected and striatum stored at -80"C if not or [] 25I]ioxipride.
Load more

Recommended publications
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • The Effect of 5-HT1A Receptor Antagonist on Reward-Based
    The Journal of Physiological Sciences (2019) 69:1057–1069 https://doi.org/10.1007/s12576-019-00725-1 ORIGINAL PAPER The efect of 5‑HT1A receptor antagonist on reward‑based decision‑making Fumika Akizawa1 · Takashi Mizuhiki1,2 · Tsuyoshi Setogawa1,2 · Mai Takafuji1 · Munetaka Shidara1,2 Received: 5 July 2019 / Accepted: 27 October 2019 / Published online: 8 November 2019 © The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2019 Abstract When choosing the best action from several alternatives, we compare each value that depends on the balance between beneft and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two diferent alternatives that were comprised of 1–4 drops of liquid reward (beneft) and 1–4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sen- sitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value. Keywords 5-HT1A · Value discounting · WAY100635 · Decision-making · Workload · Rhesus monkey Introduction comprises an iteration of simple color discriminations. The monkey can choose one of two diferent schedules to earn Whenever we choose an option from two or more alterna- promised reward.
    [Show full text]
  • Steven, Stacy (2012) the Pharmacology of the 5-HT2A Receptor and the Difficulty Surrounding Single Taret Models
    Steven, Stacy (2012) The pharmacology of the 5-HT2A receptor and the difficulty surrounding single taret models. MSc(R) thesis. http://theses.gla.ac.uk/3636/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] The pharmacology of the 5-HT2A receptor and the difficulty surrounding functional studies with single target models A thesis presented for the degree of Master of Science by research Stacy Steven April 2012 Treatment of many disorders can be frequently problematic due to the relatively non selective nature of many drugs available on the market. Symptoms can be complex and expansive, often leading to symptoms representing other disorders in addition to the primary reason for treatment. In particular mental health disorders fall prey to this situation. Targeting treatment can be difficult due to the implication of receptors in more than one disorder, and more than one receptor in a single disorder. In the instance of GPCRs, receptors such as the serotonin receptors (and in particular the 5-HT2A for the interest of this research) belong to a large family of receptors, the GPCR Class A super family.
    [Show full text]
  • Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
    Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex.
    [Show full text]
  • Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto).
    [Show full text]
  • Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
    www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Antipsychotics (Part-4) FLUOROBUTYROPHENONES
    Antipsychotics (Part-4) FLUOROBUTYROPHENONES The fluorobutyrophenones belong to a much-studied class of compounds, with many compounds possessing high antipsychotic activity. They were obtained by structure variation of the analgesic drug meperidine by substitution of the N-methyl by butyrophenone moiety to produce the butyrophenone analogue which has similar activity as chlorpromazine. COOC2H5 N H3C Meperidine COOC2H5 N O Butyrophenone analog The structural requirements for antipsychotic activity in the group are well worked out. General features are expressed in the following structure. F AR Y O N • Optimal activity is seen when with an aromatic with p-fluoro substituent • When CO is attached with p-fluoroaryl gives optimal activity is seen, although other groups, C(H)OH and aryl, also give good activity. • When 3 carbons distance separates the CO from cyclic N gives optimal activity. • The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. • AR is an aromatic ring and is needed. It should be attached directly to the 4-position or occasionally separated from it by one intervening atom. • The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol. The empirical SARs suggest that the 4-aryl piperidino moiety is superimposable on the 2-- phenylethylamino moiety of dopamine and, accordingly, could promote affinity for D2 receptors. The long N-alkyl substituent could help promote affinity and produce antagonistic activity. Some members of the class are extremely potent antipsychotic agents and D2 receptor antagonists. The EPS are extremely marked in some members of this class, which may, in part, be due to a potent DA block in the striatum and almost no compensatory striatal anticholinergic block.
    [Show full text]
  • Effects of Dopamine Receptor Antagonism and Amphetamine Sensitization on Sign- and Goal-Tracking After Extended Training
    bioRxiv preprint doi: https://doi.org/10.1101/848150; this version posted November 20, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. BioRxiv Chaudhri Lab Concordia University RESEARCH ARTICLE PREPRINT Effects of dopamine receptor antagonism and amphetamine sensitization on sign- and goal-tracking after extended training Shaun Yon-Seng Khoo1,2, Alexandra Uhrig1 and Nadia Chaudhri1,* 1Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada. and 2Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. *[email protected] Abstract Rationale. The dopamine system is thought to be important in incentive salience attribution, where motivational value is assigned to a cue that predicts an appetitive reinforcer (sign-tracking), however, dopamine’s role may change with extended training. Objectives. We tested the effects of selective dopamine D1-like and D2-like receptor antagonism on the expression of Pavlovian conditioned approach after extended Pavlovian conditioned approach (PCA) training. We also tested the hypothesis that locomotor sensitization would accelerate the phenotypic shift to sign-tracking. Methods. 24 male Long-Evans rats were subjected to 20 PCA sessions in which one lever (CS+, 10 s) predicted 0.2 mL sucrose delivery and the other lever (CS–) did not. SCH-23390 or eticlopride were administered prior to behavioral tests at doses of 0, 0.01, and 0.1 mg/kg (s.c.).
    [Show full text]
  • Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss
    Supplemental Material can be found at: /content/suppl/2020/12/18/73.1.202.DC1.html 1521-0081/73/1/202–277$35.00 https://doi.org/10.1124/pharmrev.120.000056 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:202–277, January 2021 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL NADER Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss Antonio Inserra, Danilo De Gregorio, and Gabriella Gobbi Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract ...................................................................................205 Significance Statement. ..................................................................205 I. Introduction . ..............................................................................205 A. Review Outline ........................................................................205 B. Psychiatric Disorders and the Need for Novel Pharmacotherapies .......................206 C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments . .....................................206 D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition ......208 Downloaded from E. Dissociative Anesthetics................................................................209 F. Empathogens-Entactogens . ............................................................209
    [Show full text]
  • Dopamine D2 Receptors in the Cerebral Cortex
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 6412-6416, August 1989 Neurobiology Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3Hlraclopride (raclopride binding/neostriatum/rat/monkey) MICHAEL S. LIDOW*t, PATRICIA S. GOLDMAN-RAKIC*, PASKO RAKIC*, AND ROBERT B. INNIS*f Section of *Neuroanatomy and tDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT 06510 Contributed by Pasko Rakic, May 17, 1989 ABSTRACT An apparent involvement of dopamine in the MATERIALS AND METHODS regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have fo- Tissue was obtained from three adult rhesus monkeys cused attention on the identity of cortical dopamine receptors. (Macaca mulatta): one male and two females. The animals However, only the presence and distribution of dopamine DI were anesthesized with sodium pentobarbital (40 mg/kg) and receptors in the cortex have been well documented. Compa- perfused with ice-cold phosphate-buffered saline followed by rable information on cortical D2 sites is lacking. We report here 0.1% paraformaldehyde (9; 15). The cerebral cortex and the results of binding studies in the cortex and neostriatum of neostriatum were rapidly removed and immersed in isopen- rat and monkey using the D2 selective antagonist [3H]raclo- tane at -700C for 5 min before storing at -800C until use. For pride. In both structures [3H]raclopride bound in a sodium- competition studies tissue was pooled from several neocor- dependent and saturable manner to a single population of sites tical areas. However, saturation studies were conducted on with pharmacological profiles of dopamine D2 receptors.
    [Show full text]
  • Metabolic Changes in the Rodent Brain After Acute Administration of Salvinorin a Jacob M
    B Academy of Molecular Imaging, 2009 Mol Imaging Biol (2009) 11:137Y143 Published Online: 9 January 2009 DOI: 10.1007/s11307-008-0192-x BRIEF ARTICLE Metabolic Changes in the Rodent Brain after Acute Administration of Salvinorin A Jacob M. Hooker,1 Vinal Patel,1 Shiva Kothari,1 Wynne K. Schiffer1 Medical Department, Brookhaven National Laboratory, Upton, NY, 11973, USA Abstract Purpose: Salvinorin A (SA) is a potent and highly selective kappa-opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined. Procedures: Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 2-deoxy-2-[F-18]fluoro-D-glucose (FDG), followed by image acquisition in a dedicated animal positron emission tomography (PET) system. Age-matched control animals received vehicle treatment. Animal behavior during FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis. Results: SA-treated animals demonstrated significant increases in FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerebellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory, and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during FDG uptake.
    [Show full text]