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Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 1981 Comparison of the Behavioral Pharmacology of Phencyclidine to Related Compounds Kathleen T. Brady Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medicine and Health Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/4377 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. -,. , COMPARISON OF THE BEHAV IORAL PHARMACOLOGY OF PHENCYCLIOINE TO RELATED COMPOUNDS BY Kathleen T. Brady B.S., Fordham University, 1974 submitted in partial ful fillment of the requi rements for the Degree of Doctor of Phi l osophy in the Department of Pharmacology at the Medical Col lege of Virginia Virginia Commonwealth University Richmond, Vi rginia May , 1981 This thesis by Kathleen T. Brady is accepted in its present form as satisfying the thesis requirements for the degree of Doctor of Philosoph y. Date: A roved : .�.��!��.I.. Advisor, Chairman of Graduate Committee ' · . .mry. 7.).I!?'.' ... � 7/,fl • :: ::;.•• .I •••••.••• 1 y.!.. ·'it! I -l1J · �r:t?�.�.� &} · .. /:!.'1 ?J. !. �� ( . APPROVED: .. · .. Chairman, MCV Graduate Council, Dean. School of Basic· Sciences··· .. ii CURRICULilll VITAE ';.;'; vi ACKNOWLEDGEMENTS I would especially like to thank Dr . Robert Balster for his valuabl e encouragement, friendship and guidance throughout my graduate training. I feel very fortunate to have had the opportunity to be trai ned by and work with Dr. Bal ster during the past four years. I would also like to thank the members of my committee and Dr . Everette May for their advice and suggestions during the preparation of. this manuscript. In addition, I would like to express my appreci­ ation to the members of our laboratory group, past and present, who helped make my working conditions so pleasant for the last four years and to Dr . John T. Earnhardt for his friendship, encouragement and perspective throughout. The research presented here was supported by grant DA-01 442 from the National Institute of Drug Abuse. The author was supported as a predoctoral trainee by training grant DA-07027 . To my family. for their constant encouragement and support and To John. for bel ieving in me when I didn't bel ieve in myself TABLE OF CONTENTS I. GENERAL INTRODUCTION A. History .. 1 B. Chemistry 3 C. Pharmacology 4 General Pharmacology . 4 Central Nervous System Pharmacology .--. 7 Neurotransmitter Systems . �. 7 Behavioral Pharmacology 12 Similarities in the Effects of PCP and Opioids 26 Stereospecific Effects of Opioids and Ketamine 32 Similarities in the Effects of PCP, Etoxadrol and Dexoxadro1 35 36 D. Specific Aims . II. COMPARISON OF PHENCYCLIDINE AND THREE ANALOGUES ON FIXED-INTERVAL PERFORMANCE IN RHESUS MONKEYS (EXPERIMENT I) A. Introduction 38 B. Methods 39 C. Results 43 D. Discussion 48 III. DISCRIMINATIVE STIMULUS PROPERTIES OF PHENCYCLIDINE AND FIVE ANALOGUES IN SQUIRREL MONKEYS (EXPERIMENT II) A. Introduction 62 B. Methods 65 C. Results 70 D. Discussion 75 IV. COMPARISON OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF PHENCYCLIDINE, DEXOXADROL AND ETOXADROL IN SQUIRREL MONKEYS (EXPERIMENT III) A. Introduction 82 B. Methods .. 85 C. Resu1 ts 88 D. Discussion 93 V. DISCRIMINATIVE STIMULUS PROPERTIES OF STEREOISOMERS OF N-ALLYL- NORMETAZOCINE IN PHENCYCLIDINE-TRAINED SQUIRREL MONKEYS AND RATS AND THE EFFECTS OF NALOXONE (EXPERIMENT IV) A. Introducti on . 95 B. Methods 99 C. Results .106 D. Discussion" .124 VI. DISCRIMINATIVE STIMULUS PROPERTIES OF KETAMINE STEREOISOMERS IN PCP-TRAINED RATS (EXPERIMENT V) A. Introduction .132 B. Methods .133 C. Resu1 ts .135 D. Discussion" .138 VII. STEREOSELECTIVITY IN THE DISCRIMINATIVE STIMULUS PROPERTIES OF CYCLAZOCINE IN PCP-TRAINED SQUIRREL MONKEYS (EXPERIMENT VI) A. Introduction .143 B. Methods .147 C. Results .149 D. Discuss i on . .154 VIII. FINAL DISCUSSION .158 IX. REFERENCES .169 x ABSTRACT· COMPARISON OF THE BEHAVIORAL PHARr1ACOLOGY OF PHENCYCLIDINE TO RELATED COMPOUNDS Kathl een T. Brady, Ph.D. Medical College of Virginia - Virgi nia Commonwealth University, 1981 . Major Professor: Dr. R.L. Bal ster Phencycl idine (PCP) belongs to a cl ass of drugs with � ·unique and characteristic spectra of pharmacological activity. PCP has recently -- - become a major drug of abuse. Structural anal ogues of PCP have also been reported in street use. The fol lowi ng experiments explore the behavioral pharmacology of PCP and several compounds with PCP-l ike activity. In Experiment I the effects of PCP were compared to three structural analogues in rhesus monkeys trained to lever press on a fixed-interval 5 - min schedule of food presentation. Dose-response curves and potency estimates were determined for PCP, N-ethyl -l -phenylcycl ohexyl amine (PCE), 1-(1-(2-thienyl ) cycl ohexyl ) piperidine (TCP) and ketamine. The effects of all four drugs on response rates were dependent on the basel ine rate of responding . High doses of all four drugs decreased · overall response rates . Onset and duration of drug effects were a1so. determined and compared. In Experiments II through VI the drug di scrimi nati on paradi gm was used . Animal s were trained to discriminate PCP (rats , 3.0 mg/kg i.p. ; monkeys , 0.16 mg/kg i.m.) from sal ine in a two-l ever drug discrimi nation task on a fixed- ratio 32 (FR 32) schedul e of food presentation. After rel iabl e discriminative control of lever choice was establ ished , general - ization tests were conducted every thi rd day. Test periods consisted of xi a 2-min period during which responding on either lever wa s reinforced (rats' ) or responding was recorded but not re inforced (monkeys ). The PCP dose-response determination prec�ded general ization testing with other compounds. Dose-effect curves for each drug for percent drug-lever appropriate responding and for suppression of operant responding during test sessions were analyzed by linear regression. In Experiment II the discriminative stimulus properties of PCP and- - five other arylcycloalkylamines were investigated in squirrel monkeys . Generalization testi ng was conducted wi th PCP, PCE, TCP, l-(l-phenyl cycl ohexyl ) HP), and ketamine . morpholine (PCM), l-(l_phenyl cyclohexyl ) pyrrolCdin� (P Al l drugs produced dose-dependent PCP-appropriate responding. The dose necessary to suppress operant responding to fi fty percent of vehicle rates was 3 to 8 times larger than the EDSO for drug-lever appropriate responding. Experiments III, IV and VI were designed to explore similarities between the discriminative stimulus properties of PCP and a series of structurally dissimilar compounds. In Experiment III the discrimi­ native stimulus properties of dexoxadrol and etoxadrol , both 2-(2,2� substituted 1 , 3 dioxolan-4-yl ) piperidines, were studied in squirrel monkeys. Both compounds generalized to PCP in a dose-dependent manner. The dose necessary to suppress operant responding to fifty percent of vehicle rates was 3 to 7 times larger than the EDSO dose· for drug-lever appro- priate responding. In Experiment IV the discriminative stimulus properties of stereo­ isomers of N-allyl normetazocine, a benzomorphan opioid with psychoto­ mimetic properties , were investigated in squirrel monkeys and rats . In both species, the (+) isomer and the racemic mixture produced dose­ dependent PCP-a ppropriate responding . The ( - ) isomer did not produce PCP-appropriate responding, however it wasmore potent than the (+) isomer in overall response rate suppression. High doses of naloxone (rats , 30 mg/kg ; monkeys , 1.0 and 3.0 mg/kg ) did not bl ock the drug­ lever appropriate responding or response rate suppression produced by either isomer of N-a1lynormetazocine. In Experiment the discriminative stimulus properties of ketam V i� stereoisomers were investigated in rats . Both isomers and the racemic -----­ form of ketamine produced drug-lever appropriate responding and decreased response rate in a dose-dependent manner . There was no significant potency difference between (± ) -ketamine and either of the isomers for either of these measures . The stereose1 ectivity of the discriminative stimulus properties of cyclazocine, another opioid of the benzomorphan ser ies, in squ irrel monkeys was explored in Experiment VI. The (+) isomer produced dose­ dependent PCP-appropriate responding. The ( -. ) isomer and the racem ic mixture did not produce PCP-appropriate responding at any of the doses tested . The (-1 isomer was 300 times more potent than the (+1 isomer in overall response rate suppression. The I'.Ork presented in this thesis suggests that PCP belongs to a unique class of drugs whIch can have a wide variety of chemi.cal struc.,. tures . The overa 1 pin the behav i ora 1 pharmacology of PCP and the psychotomimetic opioids of the benzomorphan series is probably due to the activity of the (+). isomers of these compounds . xiii -1- I. GENERAL INTRODUCTION The current escalation in the abuse of l-(l-phenylcyclohexyl ) piperidine (phencycl idine; PCP) has brought an increasing amount of attention to the class of drugs to which it belongs , the dissociative anesthetics. Recent research has revealed this group of compounds to have a very unique and characteristic spectra of pharmacological acti­ vity. The ·research presented in this dissertation represents an attempt to further characterize the behavioral pharmacology of this group of compounds and to make some contribution to the body of literature con­ cerned with the relationship of structure to behavioral activity. Al l compounds referred to in this thesis are racemic mixtures unless otherwise indicated. A. History· of Phencycl idine Phencycl idine (PCP) was synthesi zed by Victor Maddox and associ- ates of Parke-Davis and Co . General pharmacological testing (Chen et 21. , 1959) indicated that PCP produced surgical anesthesia in monkeys without cardiac or respiratory depression. As a result, PCP was devel­ oped by Parke-Davis and Co . as an anesthetic agent.
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  • (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday Et Al

    US 20110245287A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday et al. (43) Pub. Date: Oct. 6, 2011 (54) HYBRD OPOD COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. A6II 3/4748 (2006.01) C07D 489/02 (2006.01) (76) Inventors: John W. Holaday, Bethesda, MD A6IP 25/04 (2006.01) (US); Philip Magistro, Randolph, (52) U.S. Cl. ........................................... 514/282:546/45 NJ (US) (57) ABSTRACT Disclosed are hybrid opioid compounds, mixed opioid salts, (21) Appl. No.: 13/024,298 compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof. More particu larly, in one aspect the hybrid opioid compound includes at (22) Filed: Feb. 9, 2011 least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different Related U.S. Application Data opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical composi (60) Provisional application No. 61/302,657, filed on Feb. tions, as well as to methods of treating pain in humans using 9, 2010. the hybrid compounds and mixed opioid salts. Patent Application Publication Oct. 6, 2011 Sheet 1 of 3 US 2011/0245287 A1 Oral antinociception of morphine, oxycodone and prodrug combinations in CD1 mice s Tigkg -- Morphine (2.80 mg/kg (1.95 - 4.02, 30' peak time -- (Oxycodone (1.93 mg/kg (1.33 - 2,65)) 30 peak time -- Oxy. Mor (1:1) (4.84 mg/kg (3.60 - 8.50) 60 peak tire --MLN 2-3 peak, effect at a hors 24% with closes at 2.5 art to rigg - D - MLN 2-45 (6.60 mg/kg (5.12 - 8.51)} 60 peak time Figure 1.