1.Spin-label study of phenothiazine interactions with erythrocyte ghost membranes: a possible membrane-mediated antisickling action.
Jones GL, Woodbury DM. J Pharmacol Exp Ther. 1978 Oct;207(1):203-11.
Erythrocyte membrane alterations by 11 phenothiazine derivatives known to inhibit the sickling phenomenon in vitro have been evaluated in ghosts by the spin-labeling technique. Four sulfydryl-reactive spin labels were employed: 4-maleimido-2,2,6,6-tetramethylpiperidinooxyl; 4-(2-iodoacetamido)-2,2,6,6-tetramethylpiperidinooxyl; 3-[(2-iodoacetamido)methyl]-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl; and 3-(maleimidomethyl)-2,2,5,5-tetramethyl-1-pyrrolidiny-loxyl. The latter spin label was judged most useful since its spectrum was sensitive to subtle perturbations by drugs spanning a considerable potency range. An increase in spin-probe immobilization was induced by each drug with approximate relative potencies given by the order: desmethylchlorpromazine congruent to thioridazine congruent to fluphenazine congruent to prochlorperazine congruent to trifluoperazine greater than acetophenazine congruent to triflupromazine congruent to chlorpromazine greater than promazine greater than promethazine greater than perphenazine.
2.Anticholinergic potency of psychoactive drugs in human and rat cerebral cortex and striatum.
Danielsson E, Peterson LL, Grundin R, Ogren SO, Bartfai T. Life Sci. 1985 Apr 15;36(15):1451-7.
The affinity of selected antipsychotic and antidepressant drugs for the muscarinic receptor was studied in membranes from both human and rat striatum and cerebral cortex. While there are regional differences in the anticholinergic potency of the drugs, there is good agreement between the obtained inhibition constants from the corresponding human and rat striatum (r: 0.98) and from human and rat cerebral cortex (r: 0.96). There is also good agreement between the obtained Ki values within one species: human cerebral cortex versus human striatum (r: 0.99) and for rat cerebral cortex and rat striatum (r: 0.87). Thus, the previously published quantitative estimates of the antimuscarinic activity of psychoactive drugs which were derived from studies on membranes from rat brain give an accurate estimate of the antimuscarinic activity in human brain. The drugs tested in this study include chlorpromazine acetophenazine, haloperidol, sulpiride, remoxipride (FLA-731 (-), a substituted benzamide), amitriptyline and two serotonin uptake blockers: norzimelidine and alaproclate.
3.Titrimetric determination of some phenothiazine derivatives, with ferricyanide.
Issa AS1, Mahrous MS. Talanta. 1984 Apr;31(4):287-8.
Six phenothiazine drugs (chlorpromazine hydrochloride, promethazine hydrochloride, promazine hydrochloride, perphenazine, acetophenazine maleate and trifluoperazine hydrochloride) have been determined by titration with potassium ferricyanide in phosphoric acid medium with Methylene Blue as a screening indicator. The results were in agreement with those obtained by the official methods.
4.Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.
Bisson WH1, Cheltsov AV, Bruey-Sedano N, Lin B, Chen J, Goldberger N, May LT, Christopoulos A, Dalton JT, Sexton PM, Zhang XK, Abagyan R. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11927-32. Epub 2007 Jul 2.
Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico "drug repurposing" procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation.