Synthesis and SAR exploration of dinapsoline analogues.

Dinapsoline is a full D(1) dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was determined to have the S-(+) configuration, and the opposite enantiomer is essentially devoid of biological activity. Taken together, dinapsoline has significant metabolic and pharmacological advantages over previous D(1) agonists. In an attempt to define the structure-activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B', C and D ring) of dinapsoline were synthesized. It was found that affinity for both D(1)and D(2) receptors was decreased by most substituents on the A, B', and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.

No detectable analgesic effects in the formalin test even with one million bovine adrenal chromaffin cells.

The present experiments were conducted to identify analgesic agents for transfection into immortalized adrenal chromaffin cell lines to maximize their analgesic potential. Analgesic agents known to be produced by adrenal chromaffin cells were infused intrathecally at a low dose (0.2 microg) which might conceivably be attained by adrenal chromaffin cell transplants. Numerous agents, administered individually and in two-factor combinations, produced significant analgesic effects in the formalin test. Before assessing the potential additive or synergistic effects of these analgesic agents with adrenal chromaffin cells, studies were conducted to demonstrate analgesic effects with adrenal chromaffin cells alone. Analgesic effects were previously reported in the literature with 80-100k intrathecal bovine adrenal chromaffin (BAC) cells; but in the present study 500k purified BAC cells failed to produce detectable analgesic effects. One million purified BAC cells also failed to produce analgesic effects in the formalin test. In a final study, even nicotine-stimulated release from one million purified BAC cells failed to produce analgesic effects in the formalin test. The fact that even one million nicotine-stimulated BAC cells failed to demonstrate therapeutic potential in these blinded experiments under conditions which were clearly sensitive to the analgesic agents produced by BAC cells, raises serious questions about the clinical utility of this experimental treatment.

(+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist.

A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 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. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).