Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines
Introduction
Phenylbenzazepines are benzodiazepine analogs that include the first dopamine D1 receptor-selective agents reported (Fig. 1). The dopamine D1 receptor antagonist SCH-23390 (R[+]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine) and partial-agonist SKF-38393 (R[+]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) have had broad application as experimental probes of dopamine D1 (or D1A) receptors and the similar, but much less abundant dopamine D5 (or D1B), receptors (Neve and Neve, 1997). Phenylbenzazepines have contributed to searches for dopamine D1 receptor-based therapeutic agents including candidate antihypertensive Singh and Goyal, 1999, Mathur, 2003 and antiparkinsonism agents (Neumeyer et al., 2003) among agonists, and candidate antipsychotics among antagonists (Karlsson et al., 1995).
Dopamine D1 receptor-selective agents also include candidate treatments for psychostimulant abuse and dependence (Bergman et al., 2000). D1 receptor partial-agonists can reduce abuse-related behavioral effects of stimulants and may have less likelihood of producing either hypotension associated with full-agonists or the behavior-disrupting effects of antagonists. For example, the D1 partial-agonist SKF-83959 (R,S-3-methyl-6-chloro-7,8-dihydroxy-1-[3′-methylphenyl]-2,3,4,5-tetrahydro-1H-benzazepine; Fig. 1) has moderately high cerebral dopamine D1 receptor affinity and can reduce abuse-related behavioral effects of cocaine, including its self-administration, in monkeys Bergman and Goldberg, 1998, Khroyan et al., 2000. Moreover, such effects of SKF 83959, in contrast to other dopamine D1 receptor agonists or antagonists occur at doses with only minor disruptive effects on other behaviors Rosenzweig-Lipson and Bergman, 1994, Platt et al., 2000.
Based on previously developed phenylbenzazepines, relatively minor changes in the 3- and 3′-alkyl, and 6-halo substituents of the molecule appears to have important consequences for dopamine D1 activity (Fig. 1; Table 1). In the present study, we tested the hypothesis that changes in the 3- and 3′-alkyl, and 6-halo substituents of SKF-83959 would affect their potency and selectivity for dopamine D1 and D5 receptors.
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Materials
Receptor sources include brain tissue of adult, male Sprague–Dawley rats (Charles River Laboratories, Burlington, MA) for all assays, except that dopamine D3 and D5 receptor assays used cell membranes from Sf9 (dopamine D3 receptors) or Chinese hamster ovary (CHO; dopamine D5 receptors) cell lines transfected to express human receptor genes selectively and obtained from Sigma-RBI (Natick, MA). In addition, (+)-butaclamol, cinanserin, (−)-eticlopride, haloperidol, and phentolamine mesylate were
Results
Results of assays of potencies of 18 novel test phenylbenzazepines and seven known comparison compounds at dopamine as well as serotonin and adrenergic receptors are summarized in Table 1. The 24 phenylbenzazepines evaluated exhibited an extreme range of D1 potencies (0.11–30,000 nM), but as expected, the known comparison agents, D1 antagonist SCH-23390 and agonists SKF-38393, -77434, -81297, -82958, -83959, and R[+]-3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine (R
Discussion
The 25 substituted phenylbenzazepines evaluated are too few to support secure structure–activity assessments (Table 1). However, all of the novel agents with high dopamine D1 receptor potency had a halogen substituent at position 6: bromo- in MCL-204 and -203, chloro- in MCL-207 and -202, all of which were among the most potent dopamine D1 receptor ligands tested. Methyl-substitution on the accessory phenyl ring appeared to be optimal at position 3′ (meta), and a CF3 substituent at the same
Acknowledgments
Supported, in part, by NIDA grant DA-1311 (to JLN), an award from the Bruce J. Anderson Foundation and by the McLean Private Donors Neuropharmacology Research Fund (to RJB). Drs. James Jacob, Gerard Leclerc, Qin-Li Wu and Ao Zhang provided valuable assistance in the chemical preparation of several compounds employed in this study.
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2021, Journal of EthnopharmacologyL-DOPA promotes striatal dopamine release through D1 receptors and reversal of dopamine transporter
2021, Brain ResearchCitation Excerpt :Binding experiments in our synaptosomal preparation, however, revealed, a negligible binding of l-DOPA to D1 receptors, in agreement with previous study in D1-transfected cells (Toll et al., 1998). In our preparation, Ki values of SCH233390 (0.42 nM) and SKF38393 (29.1 nM) were in line with those previously reported in the rodent brain (SCH23390, 0.12–0.80 nM; SKF 38393, 18–41 nM) (Andersen, 1988; Neumeyer et al., 2003; Qandil et al., 2003; Watts et al., 1993). l-DOPA displaced [3H]SCH23390 binding but, different from classical D1 receptor ligands, only partially (40%).