Behavioral effects of the R-(+)- and S-( − ) enantiomers of the D 1 -like partial receptor agonist SKF 83959 in monkeys

— Dopamine D 1 -like partial receptor agonists such as SKF 83959 have been proposed as potential candidates for the treatment of cocaine addiction. The present studies were conducted to further characterize SKF 83959 by pharmacologically evaluating effects of its R -(+)- and S -( − ) enantiomers, MCL 202 and MCL 201, respectively, on overt behavior (eye blinking) and schedule-controlled performance in squirrel monkeys. MCL 202, like the D 1 full receptor agonist SKF 82958, produced dose related increases in eye blinking and decreases in rates of fixed-ratio responding. However, the magnitude of effects of MCL 202 on eye blinking was less than observed with SKF 82958. In contrast to the effects of its R -(+) enantiomer, MCL 201 was relatively devoid of behavioral activity up to doses that were approximately 10-fold greater than MCL 202. Pretreatment with the selective D 1 like receptor antagonist SCH 39166 dose-dependently antagonized increases in eye blinking produced by MCL 202, confirming the involvement of D 1 mechanisms in its effects. A dose-ratio analysis of the antagonism of effects of MCL 202 by SCH 39166 revealed an apparent pA 2 value of 7.675 with a slope of − 0.78 ± 0.04. In further studies, pretreatment with MCL 202 antagonized the effects of SKF 82958 on eye blinking and, like SCH 39166, schedule-controlled behavior in a dose-related manner. A dose-ratio analysis of the antagonist effects of MCL 202 on the SKF 82958-induced increases in eye blinking revealed ratios of 2.7, 4.8 and 31.1 for 0.1, 0.3 and 1.0 mg/kg dose of the antagonist, respectively, indicative of a significant change in the potency of SKF 82958. These results suggest that MCL 202, like its parent compound SKF 83959, has both D 1 receptor-mediated agonist and antagonist properties, consistent with its characterization as a partial agonist at the D 1 -like receptor. In addition, the inactivity of MCL 201, the S -( − )-enantiomer, suggests that the behavioral effects of SKF 83959 can be attributed primarily to the activity of its R -(+)-enantiomer. full agonist The agonist of on after the

[1]  R. I. Desai,et al.  A comparison of the locomotor stimulant effects of D1-like receptor agonists in mice , 2005, Pharmacology Biochemistry and Behavior.

[2]  R. Schwarting,et al.  Stimulation of D1- or D2-receptors in drug-naive rats with different degrees of unilateral nigro-striatal dopamine lesions , 1995, Psychopharmacology.

[3]  C. Marsden,et al.  The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease , 1995, Psychopharmacology.

[4]  C. Marsden,et al.  Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset , 1995, Psychopharmacology.

[5]  M. Packard,et al.  Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens , 1991, Psychopharmacology.

[6]  J. Witkin,et al.  Selective effects of the D1 dopamine receptor agonist, SKF 38393, on behavior maintained by cocaine injection in squirrel monkeys , 2005, Psychopharmacology.

[7]  E. Jutkiewicz,et al.  Effects of Dopamine D1 Ligands on Eye Blinking in Monkeys: Efficacy, Antagonism, and D1/D2 Interactions , 2004, Journal of Pharmacology and Experimental Therapeutics.

[8]  R. Baldessarini,et al.  Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. , 2003, European Journal of Pharmacology.

[9]  P. Terry,et al.  Comparison of the discriminative-stimulus effects of SKF 38393 with those of other dopamine receptor agonists , 2003, Behavioural pharmacology.

[10]  R. Spealman,et al.  Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development , 2002, Psychopharmacology.

[11]  A. Cools,et al.  SKF 83959 is an antagonist of dopamine D1-like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals? , 2002, Neuropharmacology.

[12]  J. Bergman,et al.  Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys , 2002, Psychopharmacology.

[13]  J. Caldwell.  Do single enantiomers have something special to offer? , 2001, Human psychopharmacology.

[14]  J. Gerlach,et al.  Aberrant behavioral effects of a dopamine D1 receptor antagonist and agonist in monkeys: evidence of uncharted dopamine D1 receptor actions , 2001, Biological Psychiatry.

[15]  R. Spealman,et al.  Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys , 2001, Psychopharmacology.

[16]  M. Nader,et al.  Modulation of cocaine's discriminative stimulus effects by dopamine D1 agonists in rhesus monkeys , 2001, Pharmacology Biochemistry and Behavior.

[17]  R. Spealman,et al.  Dissociation of cocaine-antagonist properties and motoric effects of the D1 receptor partial agonists SKF 83959 and SKF 77434. , 2000, The Journal of pharmacology and experimental therapeutics.

[18]  A. Undie,et al.  Dopaminergic behaviors and signal transduction mediated through adenylate cyclase and phospholipase C pathways , 2000, Neuropharmacology.

[19]  R. Spealman,et al.  Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior , 1999, Pharmacology Biochemistry and Behavior.

[20]  T. Kopajtic,et al.  Behavioral effects of cocaine: interactions with D1 dopaminergic antagonists and agonists in mice and squirrel monkeys. , 1999, The Journal of pharmacology and experimental therapeutics.

[21]  J. C. Stoof,et al.  Sub-chronic administration of the dopamine D1 antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys: stable therapeutic effects and wearing-off dyskinesia , 1999, Psychopharmacology.

[22]  S. B. Caine,et al.  Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. , 1999, The Journal of pharmacology and experimental therapeutics.

[23]  D. Sibley,et al.  Conservation of behavioural topography to dopamine D1-like receptor agonists in mutant mice lacking the D1A receptor implicates a D1-like receptor not coupled to adenylyl cyclase , 1999, Neuroscience.

[24]  A. Undie.  Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate–diacylglycerol accumulation in brain slices , 1999, Brain Research.

[25]  J. C. Stoof,et al.  The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors. , 1999, European journal of pharmacology.

[26]  F. J. White,et al.  Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization , 1998, Psychopharmacology.

[27]  J. Bergman,et al.  Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs. , 1998, The Journal of pharmacology and experimental therapeutics.

[28]  B. Abrahams,et al.  Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434. , 1998, European journal of pharmacology.

[29]  R. Spealman,et al.  Differential modulation of behavioral effects of cocaine by low- and high-efficacy D1 agonists , 1997, Psychopharmacology.

[30]  L. Dwoskin,et al.  The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys. , 1997, The Journal of pharmacology and experimental therapeutics.

[31]  T. Raju,et al.  Dopamine receptor sub-types involvement in nucleus accumbens and ventral tegmentum but not in medial prefrontal cortex: on self-stimulation of lateral hypothalamus and ventral mesencephalon , 1997, Behavioural Brain Research.

[32]  M. Kleven,et al.  Differential effects of direct and indirect dopamine agonists on eye blink rate in cynomolgus monkeys. , 1996, The Journal of pharmacology and experimental therapeutics.

[33]  N K Mello,et al.  Management of cocaine abuse and dependence. , 1996, The New England journal of medicine.

[34]  M. Weed,et al.  The reinforcing effects of dopamine D1 receptor agonists in rhesus monkeys. , 1995, The Journal of pharmacology and experimental therapeutics.

[35]  J. Waddington,et al.  Pharmacological characterization of behavioural responses to SK&F 83959 in relation to ‘D1‐like’ dopamine receptors not linked to adenylyl cyclase , 1995, British journal of pharmacology.

[36]  S. A. Daly,et al.  Behavioural pharmacology op ‘D-1-like’ dopamine receptors: Further subtyping, new pharmacological probes and interactions with ‘D-2-like’ receptors , 1995, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[37]  C. Marsden,et al.  Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat--relationship to circling behaviour. , 1995, Biochemical pharmacology.

[38]  R. Spealman,et al.  Differential effects of dopamine D1 and D2 receptor agonists on schedule-controlled behavior of squirrel monkeys. , 1995, The Journal of pharmacology and experimental therapeutics.

[39]  J. Witkin,et al.  Effects of D1 dopamine agonists on schedule‐controlled behavior in the squirrel monkey , 1995, Behavioural pharmacology.

[40]  H. Sarau,et al.  Evidence for a Distinct D1Like Dopamine Receptor that Couples to Activation of Phosphoinositide Metabolism in Brain , 1994, Journal of neurochemistry.

[41]  J. Waddington,et al.  Grooming and vacuous chewing induced by SK&F 83959, an agonist of dopamine 'D1-like' receptors that inhibits dopamine-sensitive adenylyl cyclase. , 1993, European journal of pharmacology.

[42]  G. Di Chiara,et al.  "Priming" to dopamine agonist-induced contralateral turning as a model of non-associative sensitization to the expression of the post-synaptic dopamine message. , 1993, Behavioural pharmacology.

[43]  L. Stein,et al.  The D1 agonists SKF 82958 and SKF 77434 are self-administered by rats , 1992, Brain Research.

[44]  R. Baldessarini,et al.  Stereoisomeric probes for the D1 dopamine receptor: synthesis and characterization of R-(+) and S-(-) enantiomers of 3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its 6-bromo analogue. , 1992, Journal of medicinal chemistry.

[45]  C. Sánchez,et al.  Partial and full dopamine D1 receptor agonists in mice and rats: relation between behavioural effects and stimulation of adenylate cyclase activity in vitro. , 1992, European journal of pharmacology.

[46]  S. A. Daly,et al.  D-1 dopamine receptors and the topography of unconditioned motor behaviour: studies with the selective, 'full efficacy' benzazepine D-1 agonist SKF 83189 , 1992, Journal of psychopharmacology.

[47]  R. Mailman,et al.  D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey. , 1991, The Journal of pharmacology and experimental therapeutics.

[48]  R. Spealman,et al.  Behavioral effects of D1 and D2 dopamine receptor antagonists in squirrel monkeys. , 1991, The Journal of pharmacology and experimental therapeutics.

[49]  W. Corrigall,et al.  Cocaine self-administration is increased by both D1 and D2 dopamine antagonists , 1991, Pharmacology Biochemistry and Behavior.

[50]  P. H. Andersen,et al.  Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy. , 1990, European journal of pharmacology.

[51]  E. Friedman,et al.  Stimulation of a dopamine D1 receptor enhances inositol phosphates formation in rat brain. , 1990, The Journal of pharmacology and experimental therapeutics.

[52]  D. Sibley,et al.  Expression of striatal D1 dopamine receptors coupled to inositol phosphate production and Ca2+ mobilization in Xenopus oocytes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Spealman,et al.  Antagonism of cocaine self‐administration by selective dopamine D1 and D2 antagonists , 1990, Behavioural pharmacology.

[54]  L. Dykstra,et al.  Discriminative and analgesic effects of mu and kappa opioids: in vivo pA2 analysis. , 1988, Psychopharmacology series.

[55]  J. Kebabian,et al.  Multiple receptors for dopamine , 1979, Nature.

[56]  L. Harris.  Problems of Drug Dependence , 1969 .

[57]  W. H. Morse,et al.  Determinants of the specificity of behavioral effects of drugs. , 1968, Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie.