Derivatives of 4-(2-N,N-Di-n-propylaminoethyl)-5-hydroxyindole: Synthesis and Pharmacological Effects
Abstract5-Methoxy-l-methyl-4-(2-N,N-di-n-propylaminoethyl)indole (12) was synthesized from 5-hydroxyindole by a multistep synthesis. This target compound was designed as a bioisostere of “p-dimethoxy” catechol congeners of dopaminergic agonists derived from a variety of ring systems, in some of which p-dimethoxy-substituted systems are potent, active dopaminergic agonists. To complete the indole series, all possible combinations of N- and O-demethylated derivatives of 12 were prepared and were also evaluated pharmacologically. All members of this indole-derived series showed a low order of cardiovascular activity, which appeared to be independent of dopamine receptors. The lack of dopaminergic activity of 12 is cited as yet another example of the unpredictable effect of replacement of the catechol moiety of a dopaminergic agonist with a p-dimethoxy moiety.
5-HT1A-receptor antagonism: N-alkyl derivatives of (R)-(-)-8,11-dimethoxynoraporphine.
Prompted by previous findings that a p-dimethoxy substitution pattern on an aromatic ring permits retention of dopaminergic agonist effects in certain ring systems, catechol derivatives of which are potent dopaminergic agonists, an 8,11-dimethoxy substitution pattern was introduced into the aporphine ring in place of the 10,11-dihydroxy moiety in apomorphine. Acid-catalyzed rearrangement of an appropriate morphine derivative provided the aporphine ring system with retention of the stereochemical integrity of the 6a asymmetric center. The hydroxyl group at position 10 was removed by catalytic hydrogenolysis of its phenyltetrazoyl ether. The methyl ether of the resulting 11-hydroxyaporphine was iodinated in high yield at position 8 with trifluoroacetyl hypiodite. This is the first account of synthesis of an iodinated aporphine derivative. The 8-iodo substituent was replaced with methoxyl by reaction with sodium methoxide and cuprous iodide. Neither the N-methyl target compound 7 nor the N-n-propyl derivative 8 demonstrated dopaminergic nor serotonergic agonism. However, 7 exhibited receptor-binding characteristics and other pharmacological properties suggesting that it may be a 5-HT1A receptor antagonist.
Therapist-case managers: more than brokers of services.
For satisfactory adjustment into the community, the long-term patient often needs assistance in dealing with a bureaucracy of agencies and departments. Some professionals have suggested establishing the role of case manager, but the case manager system is susceptible to becoming an impersonal bureaucracy itself. The author suggests that case management functions are part of the normal duties of a conscientious therapist, and that only through significant therapeutic involvement does a case manager acquire the in-depth knowledge of the patient to adequately assess his needs and facilitate the processes for meeting them. Thus the case manager should be not simply an intermediate broker of services but the patient's primary therapist. With the "therapist-case manager," the functions of therapy and case management would be combined. If therapists fail to do case management or to treat long-term patients altogether, this problem should be dealt with directly rather than simply by adding another member to the team.