8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A potent full dopamine D-1 agonist containing a rigid beta-phenyldopamine pharmacophore

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 D-1 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[alpha]phenanthridine], the first high-affinity full D-1 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 (K-I = 5.9 nM) to 3 at rat striatal D-1 receptors and had a shallow competition curve (n(H) = 0.66) that suggested agonist properties. Consistent with this, in both rat striatum and C-6-mD(1) cells, dinapsoline 4 was a full agonist with an EC(50) Of Ca 30 nM in stimulating synthesis of cAMP via D-1 receptors. The design and synthesis of dinapsoline 4 provide a powerful test of the model of the D-1 pharmacophore we have developed and provide another chemical series that can be useful probes for the study of D-1 receptors. An interesting property of 3 is that it also has relatively high D-2 affinity (K-0.5 = 50 nM) despite having an accessory phenyl ring usually thought to convey D-1 selectivity. Dinapsoline 4 was found to have even higher affinity for the D-2 receptor (K-0.5 = 31 nM) than 3. Because of the high affinity of 4 for D-2 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 D-2 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.