title: 9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: a potent full dopamine D1 agonist containing a rigid-beta-phenyldopamine pharmacophore.
abstract: The present work reports the synthesis and preliminary pharmacological characterization of 8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de] isoquinoline (4, dinapsoline). This molecule was designed to conserve the essential elements contained in our D1 agonist pharmacophore model (i.e., position and orientation of the nitrogen, hydroxyls, and phenyl rings). It involved taking the backbone of dihydrexidine [3; (+/-)-trans-10, 11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine], the first high-affinity full D1 agonist, and tethering the two phenyl rings of dihydrexidine through a methylene bridge and removing the C(7)-C(8) ethano bridge. Preliminary molecular modeling studies demonstrated that these modifications conserved the essential elements of the hypothesized pharmacopore. Dinapsoline 4 had almost identical affinity (KI = 5.9 nM) to 3 at rat striatal D1 receptors and had a shallow competition curve (nH = 0.66) that suggested agonist properties. Consistent with this, in both rat striatum and C-6-mD1 cells, dinapsoline 4 was a full agonist with an EC50 of ca. 30 nM in stimulating synthesis of cAMP via D1 receptors. The design and synthesis of dinapsoline 4 provide a powerful test of the model of the D1 pharmacophore we have developed and provide another chemical series that can be useful probes for the study of D1 receptors. An interesting property of 3 is that it also has relatively high D2 affinity (K0.5 = 50 nM) despite having an accessory phenyl ring usually though to convey D1 selectivity. Dinapsoline 4 was found to have even higher affinity for the D2 receptor (K0.5 = 31 nM) than 3. Because of the high affinity of 4 for D2 receptors, it and its analogs can be powerful tools for exploring the mechanisms of "functional selectivity" (i.e., that 3 is an agonist at some D2 receptors, but an antagonist at others). Together, these data suggest that 4 and its derivatives may be powerful tools in the study of dopamine receptor function and also have potential clinical utility in Parkinson's disease and other conditions where perturbation of dopamine receptors is useful.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ghosh
authors.forename: S E
authors.initials: SE
authors.lastname: Snyder
authors.forename: V J
authors.initials: VJ
authors.lastname: Watts
authors.forename: R B
authors.initials: RB
authors.lastname: Mailman
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009284:Naphthols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007546:Isoquinolines; D009284:Naphthols; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C097827:dinapsoline; D000242:Cyclic AMP; D000262:Adenylyl Cyclases