8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A potent full dopamine D₁ agonist containing a rigid β-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 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 (K(I) = 5.9 nM) to 3 at rat striatal D₁ 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-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 (K_0.5 = 50 nM) despite having an accessory phenyl ring usually thought to convey D₁ selectivity. Dinapsoline 4 was found to have even higher affinity for the D₂ receptor (K_0.5 = 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.