Lymphocyte responsiveness in rats was found to depend on serum prolactin levels. Blocking pituitary prolactin release with bromocriptine severely reduces lymphocyte reactivity in vitro (mixed lymphocyte reaction) as well as in vivo (graft-versus-host reaction). In addition, evidence for a prolactin/growth hormone-related mRNA species produced in mitogen-and antigen-stimulated lymphocytes has been obtained. Prolactin was shown to compete in a dose-dependent fashion with the immunosuppressant cyclosporine (cyclosporin A) for a common binding site on the surface of T lymphocytes. Further, stimulation of prolactin secretion reversed the immunosuppression induced by cyclosporine. We conclude that prolactin is involved in the maintenance of T-cell immunocompetence and that the immunosuppressive effects of cyclosporine may be mediated by the displacement of prolactin from binding sites on lymphocytes.

A synthesis of all four diastereoisomeric 3-(tert-butoxycarbonyl)-1,6-dimethoxyoctahydrobenzo[g]quinolines 13a-d is presented. The two trans isomers 13b and 13c have been converted to tricyclic analogues 20 (CV 205-502) and 26 (205-503) of the potent dopaminomimetic ergolines CQ 32-084 and pergolide, respectively. These two compounds combine the essential moiety of apomorphine with the important 8-substituents of ergolines. Preliminary pharmacological evaluation of 20 and 26 suggests that these novel dopamine agonists combine the specificity of apomorphine with the potency, long duration of action, and good oral activity of the ergolines.

Background:Taxol, a promising agent for the treatment of cancer, has entered phase II clinical trials. Nevertheless, it belongs to the class of compounds that show impaired retention in multidrug-resistant cells expressing P-glycoprotein (Pgp), a drug efflux pump. Chemosensitizers like verapamil modulate multidrug resistance by interfering with the efflux action of Pgp and thus can decrease drug resistance or can restore drug sensitivity by restoring normal drug accumulation and distribution within the multidrugresistant tumor cell. The two strongest, nearly equipotent chemosensitizers identified to date are the cyclosporine derivative SDZ PSC 833 and the semisynthetic cyclopeptolide SDZ 280-446. Purpose: This study was designed to investigate the capacities of verapamil, SDZ PSC 833, and SDZ 280-446 to decrease resistance of two multidrug-resistant cell lines to taxol. Methods: We studied in vitro the growth of two multidrugresistant tumor cell lines displaying high resistance to taxol: multidrugresistant Chinese hamster ovary cells

Step of the Corrin Synthesis via A ! D Ring Closure D: The Photochemical A/D-Secocorrin ! Corrin Cycloisomerization: Exploratory Studies on its Mechanism.Chapter A describes the background of the two topics discussed in Chapts. B and C within the general context of the project Corrin Syntheses.Chapter B deals with the development and application of C,C-bond formation by sulfide contraction as a general method for constructing the chromophore system in corrin ligands. The method had been developed in the context of the task of joining precursors of ring B and ring C to the B/C component in the collaborative Harvard/ ETH project of the synthesis of vitamin B 12 . Conceptually, the methods central process corresponds to an intramolecularization of an otherwise intermolecular C,C-bond formation by a (thio)imido-ester/enamine (enamide) condensation. The procedure starts by a preliminary intermolecular oxidative coupling of the S-atom of a thiolactam group with the electrophilic C-center of an enamine or enamide group to give an imidoyl-vinyl-sulfide intermediate, which, in a follow-up step, is intramolecularly contracted to a vinylogous amidine system with concomitant transfer of the S-atom to an external thiophile (cf. Fig. 3). The method has been successfully applied to the construction of A/D-secocorrin model substrates in three model series by three different strategies of connecting the four peripheral rings A, B, C and D. These strategies differ in the sequence by which these four rings are joined together (cf. Figs. 5 and 6, 10 and 11, and 13). A/D-Secocorrin complexes obtained by a B þ C ! BC þ A ! ABC þ D ! ABCD strategy served as main model substrates for the exploration of the photochemical A/D-secocorrin ! corrin cycloisomerization, whereas an A/Dsecocorrin chloro-Zn II complex constructed by a BC þ D ! BCD þ A ! ABCD strategy was the target of a model study pursued as a pacemaker synthesis for the construction of the chromophore system in the photochemical variant of the vitamin B 12 synthesis.In Chapt. C, the targeted discovery and some of the applications of the photochemical A/D-secocorrin ! corrin cycloisomerization are described. The concept of this novel process emerged for a corrin synthesis in which all four rings are derived from one single starting material, reflecting the hidden structural symmetry of the vitamin B 12 molecule. The reaction was studied in three A/D-secocorrin model systems (cf. Chapt. A), the A/D-secocorrin model in the 15-cyano-2,2,7,7,12.12-hexamethyl-1methylidene series being the one that served as the main substrate in the exploration of the reaction. The A ! D ring closure proceeded smoothly under the influence of visible light and under strict exclusion of O 2 in yields of over 90% in A/D-secocorrin complexes of the filled-shell metal ions Zn II , Cd II , Mg II , Li I , and (tentatively) also Ca II and Na I , but not for complexes of the first-row transition metals such as Ni II , Cu II , and (tentatively) Co III , Mn II , and Fe II . The reaction also occurs -more slowly...

Mesulergine, an 8-alpha-aminoergoline, is now proven to be of utility in the clinic as an antiparkinsonian drug. However, the molecule itself shows in vitro and in vivo antidopaminergic properties. Mesulergine is rapidly metabolized into several pharmacologically active DA agonists. The influence of mesulergine on central DA metabolism in rats is dependent on the route of drug administration. It was possible to determine the different metabolites of this drug in plasma as well as in rat striatum. A correlation between the actual present concentration of the parent drug and DAergic metabolites and the net action on striatal DA metabolism was found. It may be concluded that mesulergine itself lacks DAergic activity but occupies DA receptors and is very rapidly metabolized into potent DA agonists.