Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D1 dopamine receptor. In addition to its full D1 agonist properties, 2 also is a good ligand for D2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D1 and D2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D1 receptor labeled by [3H]SCH23390 (K0.5s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D1 receptors expressed in transfected Ltk- cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 microM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 microM for the (-)-enantiomer. Together, these data demonstrate that both the D1 and D2 activities of dihydrexidine reside principally in the (6aR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D1 receptor.

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Dihydrexidine [4;(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8, 12b-hexahydrobenzo[a]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (+/-)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8, 12b-hexahydrobenzo[a]phenanthridine (5) was a high-affinity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[a]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.

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Biodiesel is an important alternative fuel synthesized by the trans-esterification of vegetable oils, animal fats, and recycled greases. In this experiment, students prepared biodiesel through the base-catalyzed trans-esterification of several vegetable oils, which were subsequently analyzed in comparison with conventional petroleum-based fuels to assess their physical properties and to obtain a thermochemical profile. The experiment as described here could be employed by university faculty as a project in a major's level laboratory course, but we envision the ideal fit to be a module within an advanced or integrated laboratory course. Students completing the project gain valuable experience in chemical synthesis and in extensive product characterization and analysis. This project reinforces critical skills in isolation of pure products from complex mixtures and in the careful preparation of samples for chemical analysis. Finally, students are afforded the opportunity to compare theoretical predictions from chemical modeling in combination with GC−MS analysis with the practical results gained by performing bomb calorimetry.