Showing papers in "Journal of Natural Products in 1995"
TL;DR: A discussion of policies for international collaboration and compensation being implemented by several developed country organizations, and the perspectives on the current developments given by representatives of some of the source countries located in the regions of greatest biodiversity.
Abstract: Until recently, the prevailing attitude in developed nations regarded the world's genetic resources, which are mainly concentrated in the developing world, as a common resource of humankind, to be exploited freely irrespective of national origin. With the devastation being wreaked in the tropical rainforests and the resurgence in interest in recent years in the discovery of novel drugs from natural sources, particularly plants and marine organisms, the international scientific community has realized that the conservation of these global genetic resources and the indigenous knowledge associated with their use are of primary importance if their potential is to be fully explored. With this realization has come a recognition that these goals must be achieved through collaboration with, and fair and equitable compensation of, the scientists and communities of the genetically rich source countries. The signing of the United Nations Convention on Biological Diversity by nearly all of the World's nations has emphasized the need for the implementation of such policies. In this review, the articles of the Convention of relevance to the activities and practices of the natural products scientific community are briefly discussed. This discussion is followed by a summary of policies for international collaboration and compensation being implemented by several developed country organizations, and the perspectives on the current developments given by representatives of some of the source countries located in the regions of greatest biodiversity.
359Â citations
TL;DR: Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme.
Abstract: Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2, C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme. These results are of use for the selection of flavonoids that can inhibit specific topoisomerases at specific stages of the topoisomerization reaction.
268Â citations
TL;DR: Immunoassay techniques are currently being used to screen extracts of Taxomyces andreanae for new taxanes, and to determine if other endophytic fungi are taxol producers, which appears to produce taxol and other taxanes in de novo fashion when grown in semi-synthetic liquid media.
Abstract: Endophytic microbes associated with the Pacific yew tree, Taxus brevifolia, were examined as potential sources of the anticancer drug taxol [1], a secondary metabolite of the host organism. The first promising organism found was the novel fungus, Taxomyces andreanae, which was isolated from the inner bark of a yew tree growing in northwestern Montana. It appears to produce taxol and other taxanes in de novo fashion when grown in semi-synthetic liquid media. The presence of 1 in the fungal extract was confirmed by mass spectrometry, comparative chromatographic behavior with "yew" taxol, reactivity with taxol-specific monoclonal antibodies, and 9KB cytotoxicity studies. Both acetate-1-14C and phenylalanine UL-14C served as precursors of taxol-14C in fungal culture labeling studies, confirming the de novo synthesis of 1 by the fungus. Immunoassay techniques are currently being used to screen extracts of Taxomyces andreanae for new taxanes, and to determine if other endophytic fungi are taxol producers.
240Â citations
TL;DR: The isoflavones daidzein and genistein were fermented with human fecal bacteria under anaerobic conditions and metabolites 3-6 were identified by spectral methods.
Abstract: The isoflavones daidzein [1] and genistein [2] were fermented with human fecal bacteria under anaerobic conditions. Dihydrodaidzein [3], benzopyran-4,7-diol,3-(4-hydroxyphenyl) [4], and equol [5] were isolated from the fermentation broth of 1. Only one metabolite, dihydrogenistein [6], was isolated and characterized from the fermentation broth of 2. Metabolites 3-6 were identified by spectral methods.
180Â citations
TL;DR: Three new steroids, zhankuic acids A, B and C, were isolated from the fruiting bodies of Antrodia cinnamomea by bioassay-guided fractionation and exhibited cytotoxic activity against P-388 murine leukemia cells and weak anticholinergic and antiserotonergic activities.
Abstract: Three new steroids, zhankuic acids A [1], B [2], and C [3], were isolated from the fruiting bodies of Antrodia cinnamomea by bioassay-guided fractionation. The structures of these compounds were elucidated by chemical reactions and detailed analysis of their 1H- and 13C-nmr spectra. Biological studies revealed that 1 exhibited cytotoxic activity against P-388 murine leukemia cells and 2 showed weak anticholinergic and antiserotonergic activities.
164Â citations
TL;DR: Two tris-indole alkaloids have been isolated for the first time from a marine source, the New Caledonian sponge, and showed anti-serotonin activity and a strong affinity for somatostatin and neuropeptide Y receptors in receptor-binding assays.
Abstract: Two tris-indole alkaloids, (+/-) gelliusines A and B [1], have been isolated for the first time from a marine source, the New Caledonian sponge, Orina sp. (or Gellius sp.), along with five further indole constituents [2-6]. Compound 6 has been identified as 2,2-bis-(6'-bromo-3'-indolyl(-ethylamine, previously isolated from the tunicate Didemnum candidum, but the remaining four indoles [2-5] are novel compounds. These showed anti-serotonin activity and a strong affinity for somatostatin and neuropeptide Y receptors in receptor-binding assays.
144Â citations
TL;DR: Interestingly, all six diketopiperazines in the cyanobacteria-containing Caribbean sponge are proline-derived cyclic dipeptides, the first example for this class of peptide derivative to be isolated from a Calyx sponge.
Abstract: The cyanobacteria-containing Caribbean sponge, Calyx cf. podatypa, was collected from three sites in the Bahamas. In each of the three collections, a polar solvent partition fraction contained six known compounds including five diketopiperazines [1-4,6] and phenylacetic acid, along with a new diketopiperazine, cyclo-(4-methyl-R-proline-S-norvaline) [5]. Interestingly, all six diketopiperazines are proline-derived cyclic dipeptides. This is the first example for this class of peptide derivative to be isolated from a Calyx sponge. Parallel studies of one of the sponge collections in which the ectosome (cyanobacteria-rich) was separated from the endosome (no cyanobacteria) revealed no significant differences in their content of diketopiperazines.
134Â citations
TL;DR: In an in vitro cell culture assay, pectenotoxin II and psammaplin A displayed very potent cytotoxic activities against human lung (A-549), colon (HT-29), and breast (MCF-7) cancer cell lines.
Abstract: Investigation of the cytotoxic constituents of a two-sponge association (Poecillastra sp. and Jaspis sp.) led to the isolation of pectenotoxin II [1] and psammaplin A as the active compounds. In an in vitro cell culture assay, 1 displayed very potent cytotoxic activities against human lung (A-549), colon (HT-29), and breast (MCF-7) cancer cell lines. Pectenotoxin II also exhibited selective cytotoxicity against several cell lines representing ovarian, renal, lung, colon, CNS, melanoma, and breast cancer, with differences in LC 50 values between sensitive and resistant cell lines of 100-fold or more
130Â citations
129Â citations
TL;DR: The mechanism of action of 1 beta-hydroxyaleuritolic acid 3-p-Hydroxybenzoate and protolichesterinic acid as HIV-1 RT inhibitors involves nonspecific binding to the enzyme at nonsubstrate binding sites, whereas swertifrancheside inhibits enzyme activity by binding toThe template-primer.
Abstract: Swertifrancheside [1], a new flavonone-xanthone glucoside isolated from Swertia franchetiana, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2], a triterpene isolated from the roots of Maprounea africana, and protolichesterinic acid [3], an aliphatic alpha-methylene-gamma-lactone isolated from the lichen Cetraria islandica, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT), with 50% inhibitory doses (IC50 values) of 43, 3.7, and 24 microM, respectively. They were not cytotoxic with cultured mammalian cells. The kinetic mechanisms by which compounds 1-3 inhibited HIV-1 RT were studied as was their potential to inhibit other nucleic acid polymerases. Swertifrancheside [1] bound to DNA and was shown to be a competitive inhibitor with respect to template-primer, but a mixed-type competitive inhibitor with respect to TTP. On the other hand, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] were mixed-type competitive inhibitors with respect to template-primer and noncompetitive inhibitors with respect to TTP. Therefore, the mechanism of action of 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] as HIV-1 RT inhibitors involves nonspecific binding to the enzyme at nonsubstrate binding sites, whereas swertifrancheside [1] inhibits enzyme activity by binding to the template-primer.
121Â citations
TL;DR: A known aporphine alkaloid, (-)-roemerine, isolated from the leaves of Annona senegalensis, was found to enhance the cytotoxic response mediated by vinblastine with multidrug-resistant KB-V1 cells.
Abstract: A known aporphine alkaloid, (-)-roemerine [1], isolated from the leaves of Annona senegalensis, was found to enhance the cytotoxic response mediated by vinblastine with multidrug-resistant KB-V1 cells. In the absence of vinblastine, no significant cytotoxicity was observed with KB-3 or KB-V1 cells (ED50 > 20 micrograms/ml), and several other human tumor cell lines were also relatively insensitive. As indicated by its ability to inhibit ATP-dependent [3H]vinblastine binding to multidrug-resistant KB-V1 cell membrane vesicles, (-)-roemerine appears to function by interacting with P-glycoprotein. In addition to alkaloid 1, three inactive compounds [the aporphine alkaloid(-)-isocorydine (reported in the levo-configuration for the first time), and the lignans (+/-)-8,8'-bisdihydrosiringenin [2] (a new natural product), and (+)-syringaresinol] were also isolated.
TL;DR: Extracts and pure compounds isolated from four samples of Dysidea sp.
Abstract: Extracts and pure compounds isolated from four samples of Dysidea sp sponges collected from two geographically distinct regions of the Indo-Pacific (Chuuk Atoll and Fiji) were assayed against five different enzyme assays, four of which are relevant to anticancer drug discovery and one of which (15-lipoxygenase) may detect compounds significant in modulating the development of atherosclerotic plaque The pure compounds that inhibited various enzymes were polybrominated phenols and polybrominated phenoxyphenols Fourteen of these phenols were isolated, six of which were new compounds A variety of the phenols inhibited inosine monophosphate dehydrogenase (IMPDH), guanosine monophosphate synthetase, and 15-lipoxygenase No activity was observed with protein tyrosine kinase pp60v-src or matrix metalloprotease
TL;DR: Results indicate that Weir vine poisoning is an additional manifestation of the induced lysosomal storage disease, mannosidosis, possibly exacerbated by inhibition of the enzymes beta-glucosidase and alpha-galactosidases by calystegine B2.
Abstract: The polyhydroxy alkaloid glycosidase inhibitors swainsonine [1] and calystegine B2 [6] have been identified as constituents of the seeds of the Australian plant Ipomoea sp Q6 [aff calobra] (Weir vine) by gas chromatography-mass spectrometry and by their biological activity as inhibitors of specific glycosidases This plant, which is known only from a small area of southern Queensland, has been reported to produce a neurological disorder when consumed by livestock The extract of the seeds showed inhibition of alpha-mannosidase, beta-glucosidase, and alpha-galactosidase, consistent with the presence of 1 and alkaloids of the calystegine class Histological examination of brain tissue from field cases of sheep and cattle poisoned by Weir vine showed lesions similar to those observed in animals poisoned by the swainsonine-containing poison peas (Swainsona spp) of Australia and locoweeds (Astragalus and Oxytropis spp) of North America These results indicate that Weir vine poisoning is an additional manifestation of the induced lysosomal storage disease, mannosidosis, possibly exacerbated by inhibition of the enzymes beta-glucosidase and alpha-galactosidase by calystegine B2 This is the first reported example of a single plant species capable of producing structurally distinct glycosidase inhibitors, namely, alkaloids of the indolizidine and nortropane classes
TL;DR: Three caffeoylquinic acids, isolated from the Peruvian plants Tessaria integrifolia and Mikania cordifolia, exhibited an appreciable anti-inflammatory activity in vitro, while the tricaffeoyl derivative was inactive.
Abstract: Three caffeoylquinic acids, isolated from the Peruvian plants Tessaria integrifolia and Mikania cordifolia that are used medicinally as anti-inflammatory agents, were tested for their activities on monocyte migration and superoxide anion production. 3,5-Di-O-caffeoylquinic and 4,5-di-O-caffeoylquinic acids exhibited an appreciable anti-inflammatory activity in vitro, while the tricaffeoyl derivative was inactive.
TL;DR: Pseudolaric acid B was active against Trichophyton mentagrophytes, Torulopsis petrophilum, Microsporum gypseum, and Candida spp.
Abstract: Pseudolaric acid B [1] was isolated and identified as the main antifungal constituent of Pseudolarix kaempferi using bioassay-directed fractionation. Pseudolaric acid B was active against Trichophyton mentagrophytes, Torulopsis petrophilum, Microsporum gypseum, and Candida spp., while its methylated or hydrolyzed derivatives were not active against these same organisms. The minimum inhibitory concentrations and minimum fungicidal concentrations of pseudolaric acid B [1] against Candida and Torulopsis species were comparable with those of amphotericin B. The in vivo activity of pseudolaric acid B was evaluated in a murine model of disseminated candidiasis. Pseudolaric acid B [1] reduced the number of recovered colony-forming units significantly at different dosages. Infected mice treated intravenously with pseudolaric acid B [1] also had a longer survival time than those treated with vehicle alone.
TL;DR: Fourteen norditerpenoid alkaloids present in larkspur (Delphinium) species associated with cattle poisoning on grazing land in the western United States have been toxicologically assessed in a mouse bioassay and the relationship of the structure-activity information to previous in vitro neuromuscular studies is discussed.
Abstract: Fourteen norditerpenoid alkaloids present in larkspur (Delphinium) species associated with cattle poisoning on grazing land in the western United States have been toxicologically assessed in a mouse bioassay. Toxicity data for these alkaloids have established the tertiary nitrogen atom and anthranilic acid esterification as important structural features necessary to impart toxicity to lycoctonine-type norditerpenoid alkaloids. Variation in C-14 functionality of the toxic alkaloids is also a factor that influences toxicity in these compounds. The relationship of the structure-activity information of this study to previous in vitro neuromuscular studies is discussed.
TL;DR: Two types of antibiotics, namely, indoles and dithiolopyrrolones, have been isolated and identified from Xenorhabdus bovienii A2 and showed strong activity against Cryptococcus neoformans and Botrytis cinerea and Phytophthora infestants.
Abstract: Two types of antibiotics, namely, indoles and dithiolopyrrolones, have been isolated and identified from Xenorhabdus bovienii A2. Compounds 1 and 2 showed strong activity against Cryptococcus neoformans, compounds 3 and 4 showed strong activity against Botrytis cinerea, and compounds 1, 3, and 4 showed significant activity against Phytophthora infestants (2 was not tested). In addition, two lower homologues of xenorhabdins 5 and 6, namely, 6-(N-3'-methylbutanamido)-4,5-dihydro-1,2-dithiolo[4,3-b]pyr rol-5- one [7] and 6-(N-butanamido)[4,5-dihydro-1,2-dithiolo[4,3-b]pyrrol-5-one [8], have been isolated and characterized for the first time.
TL;DR: An extract of Cryptolepis sanguinolenta yielded five alkaloids, two of which were the known compounds cryptolepine and quindoline and three of which have not been reported previously and were named hydroxycryptolepine, cryptoheptine, and cryptoquindoline.
Abstract: An extract of Cryptolepis sanguinolenta yielded five alkaloids. Two of these were the known compounds cryptolepine [1] and quindoline [2]. Three of the compounds have not been reported previously and were named hydroxycryptolepine [3], cryptoheptine [4], and cryptoquindoline [5]. Compound 5 was shown to be an artifact.
TL;DR: Treatment of 1-4 with dilute HCl yielded known caffeic acid tetramers [8 and 9], which were found to be less active, indicating the importance of the sodium and potassium salts to the enhanced anti-HIV activity.
Abstract: Monosodium and monopotassium salts [2-4] of isomeric caffeic acid tetramers were isolated from Arnebia euchroma as anti-HIV agents. Mixtures of dipotassium and disodium salts [1] of a caffeic acid tetramer and dipotassium and potassium-sodium salts [5] of a caffeic acid tetramer glucoside were also isolated from the active fraction. The structures of 1-5 were characterized by chemical and spectral evidence. Compounds 2-4 demonstrated potent anti-HIV activity with EC50 values of 2.8, 4.0, and 1.5 micrograms/ml, respectively. Treatment of 1-4 with dilute HCl yielded known caffeic acid tetramers [8 and 9], which were found to be less active, indicating the importance of the sodium and potassium salts to the enhanced anti-HIV activity.
TL;DR: The results obtained suggest that molecules possessing free alcoholic or phenolic groups showed the most potent acaricidal activity.
Abstract: The pharmacological activity of many essential oils on a large number of human and animal pathogens, as used in folk medicine, has been confirmed world-wide by several laboratory investigations. Unfortunately, the biological properties of essential oils can be extremely inconsistent because of the variability of their chemical composition. The acaricidal activities of some natural terpenoids, which are the main constitutents of several essential oils, were evaluated in vitro against the mange mite (Psoroptes cuniculi) of the rabbit, by direct contact and by inhalation. Because the test components represent different chemical classes (hydrocarbons, alcohols, and phenols, with free and esterified or etherified functional groups), it was also possible to discern in a preliminary fashion a correlation between chemical structure and acaricidal activity. The results obtained suggest that molecules possessing free alcoholic or phenolic groups showed the most potent acaricidal activity.
TL;DR: A number of metabolites of daidzein and genestein have been synthesized and their biological activities determined, with equol being the most active of the compounds tested against topoisomerase I.
Abstract: A number of metabolites of daidzein and genestein have been synthesized and their biological activities determined. Equol [3], 5,7,4'-trihydroxyisoflavan [5], 4,7,4'-trihydroxyisoflavan [6], dihydrodaidzein [8], and dihydrogenistein [9] were synthesized either from daidzein [1] or genistein [2] by hydrogenation. Similarly, the derivatives 4, 7, and 11 were synthesized from 3, 6, and 10, respectively. During acetylation and nmr experiments, 9 was converted to a novel enol intermediate [10]. Antifungal, antibacterial, mosquitocidal, nematocidal, and topoisomerase inhibition activities of these compounds were evaluated, with equol [3] being the most active of the compounds tested against topoisomerase I.
TL;DR: Seven new pyrroloiminoquinone alkaloids, makaluvamines H-M, and damirone C, together with the known compounds, were isolated from the sponge Zyzzya fuliginosa collected at Nahpali Island, Pohnpei, Micronesia.
Abstract: Seven new pyrroloiminoquinone alkaloids, makaluvamines H-M [19-24] and damirone C[25], together with the known compounds, makaluvamines C[13], D[14], and G[17], were isolated from the sponge Zyzzya fuliginosa collected at Nahpali Island, Pohnpei, Micronesia. The structures of the new compounds were elucidated by interpretation of spectral data. The chemotaxonomic relationships involving the makaluvamines and related pyrroloiminoquinone alkaloids are discussed.
TL;DR: In laboratory feeding experiments, crude extracts and purified amphitoxin from A. compressa at lower than natural concentration levels effectively deterred feeding of a generalist predatory Caribbean reef fish, Thalassoma bifasciatum.
Abstract: A new polymeric pyridinium alkaloid named amphitoxin [2] has been isolated from Amphimedon compressa, and its structure determined by spectroscopic analysis. In laboratory feeding experiments, crude extracts and purified amphitoxin [2] from A. compressa at lower than natural concentration levels effectively deterred feeding of a generalist predatory Caribbean reef fish, Thalassoma bifasciatum.
TL;DR: The sponge Dysidea fragilis from Pohnpei contained four azacyclopropene derivatives, which is the optical enantiomer of the known compound dysidazirine, and the structures of the new compounds were elucidated by interpretation of spectral data.
Abstract: The sponge Dysidea fragilis from Pohnpei contained four azacyclopropene derivatives, (4E)-S-dysidazirine [2], which is the optical enantiomer of the known compound dysidazirine [1], (4Z)-dysidazirine [3], (4E)-S-antazirine [4], and (4Z)-antazirine [5]. The structures of the new compounds were elucidated by interpretation of spectral data.
TL;DR: The leaves of Annona muricata have yielded eight monotetrahydrofuran Annonaceous acetogenins; two of them, annomuricins A and B, are novel and unusual.
Abstract: The leaves of Annona muricata have yielded eight monotetrahydrofuran Annonaceous acetogenins. Two of them, annomuricins A [1] and B [2], whose chemical structures were deduced by ms, nmr, ir, and uv spectral and chemical methods, are novel and unusual. Compounds 1 and 2 each possess five hydroxyl groups; two hydroxyl groups are vicinal, with the vicinal group of 1 threo and that of 2 erythro. The absolute configurations of 1 and 2 were determined by Mosher ester methodology. Six monotetrahydrofuran acetogenins, previously described in the seeds, were found in the leaves; these are gigantetrocin A, annonacin-10-one, muricatetrocins A and B, annonacin, and goniothalamicin.
TL;DR: Bioactivity-guided fractionation of a chloroform extract of the soft coral Simularia gibberosa afforded a new cytotoxic cembranoid diterpene, sinugibberol, which was determined by spectral and X-ray crystallographic analysis.
Abstract: Bioactivity-guided fractionation of a chloroform extract of the soft coral Simularia gibberosa afforded a new cytotoxic cembranoid diterpene, sinugibberol [1]. The structure of 1 was determined by spectral and X-ray crystallographic analysis.
TL;DR: The leaves of Ilex paraguariensis have yielded three new saponins named matesaponins 2, 3, and 4, which have been characterized by chemical and nmr methods as ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-[alpha-L-rhamnopyrnosyl- (1-->2)]]-alpha- L-arabinopyranusyl]-(28-->1)-beta-
Abstract: The leaves of Ilex paraguariensis have yielded three new saponins named matesaponins 2, 3, and 4 [1-3], which have been characterized by chemical and nmr methods as ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-[alpha-L-rhamnopyranosyl- (1-->2)]]-alpha-L-arabinopyranosyl]-(28-->1)-beta-D-glucopyranosyl ester, ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-alpha-L-arabinopyranosyl]-(28-- >1)- [beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]ester, and ursolic acid 3-O-[beta-D-glucopyranosyl-(1-->3)-[alpha-L- rhamnopyranosyl-(1-->2)]]-alpha-L-arabinopyranosyl]-(28-->1)-[beta -D- glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]ester, respectively
TL;DR: Varacin and three new antimicrobial marine polysulfides, varacins A-C [3-5], have been isolated from the Far Eastern ascidian Polycitor sp.
Abstract: Varacin [1] and three new antimicrobial marine polysulfides, varacins A-C [3-5], have been isolated from the Far Eastern ascidian Polycitor sp. Their structures have been elucidated by spectroscopic methods and by chemical transformations.
TL;DR: The novel phorbol ester 12-deoxyphorbol 13-(3E,5E-decadienoate) [1] was isolated as the anti-HIV principle of Excoecaria agallocha leaves and stems collected in northwest Australia by spectral means.
Abstract: The novel phorbol ester 12-deoxyphorbol 13-(3E,5E-decadienoate) [1] was isolated as the anti-HIV principle of Excoecaria agallocha leaves and stems collected in northwest Australia. The structure was determined by spectral means. Compound 1 was also a potent displacer of [3H]-phorbol dibutyrate from rat brain membranes.