bluuebunny/crossref_metadata_2025_split huggingface dataset:
An examination of deoxyadenosine 5′(α‐thio)triphosphate as a ligand to define P2Y receptors and its selectivity as a low potency partial agonist of the P2Y1 receptor
Authors: Schachter Joel B , Kendall Harden T 
Published: August 2006

The functional activity of deoxyadenosine 5′(α‐thio)triphosphate (dATPαS) was assessed at the cloned human P2Y1 receptor stably expressed in 1321N1 human astrocytoma cells and transiently expressed in Cos‐7 cells.
Cells expressing the receptor responded to adenine nucleotides with an increase in [3H]‐inositol phosphate accumulation. Half‐maximal responses were obtained at approximately 30 nM for 2‐methylthioadenosine‐5′‐triphosphate (2MeSATP), 300 nM for dATPαS, and 1000 nM for adenosine 5′‐triphosphate (ATP). dATPαS produced a maximal response that was only 37±4% of that produced by ATP or 2MeSATP. dATPαS also competitively antagonized the phospholipase C response to 2MeSATP with a KB of 644±14 nM. Thus dATPαS acts as a low potency partial agonist at P2Y1 receptors.
The selectivity of dATPαS for P2Y1 receptors was determined by examining its capacity to activate P2Y2, P2Y4 and P2Y6 receptors also stably expressed in 1321N1 cells. Although dATPαS was a partial agonist at P2Y1 receptors it was a full agonist at P2Y2 receptors, albeit with a potency that was two orders of magnitude lower than at P2Y1 receptors. No agonist or antagonist activity was observed at P2Y4 and P2Y6 receptors.
Although [35S]‐dATPαS bound to a relatively high density (ca 10 pmol mg−1 protein) of binding sites in membranes from 1321N1 or Cos‐7 cells expressing the P2Y1 receptor, no difference in the total density of sites was observed between membranes from wild‐type, empty vector‐transfected, or P2Y1 receptor‐expressing cells. Moreover, adenine nucleotide analogues inhibited [35S]‐dATPαS binding with an order of potency that differed markedly from that for the accumulation of inositol phosphates in intact transfected P2Y1 receptor‐expressing cells. Saturation binding experiments demonstrated multiple affinity states for [35S]‐dATPαS binding in wild‐type Cos‐7 cell membranes. These data from 1321N1 and Cos‐7 cells suggest that cellular membranes exhibit a large number of high affinity binding sites for [35S]‐dATPαS that are not related to P2Y receptor subtypes.

British Journal of Pharmacology (1997) 121, 338–344; doi:10.1038/sj.bjp.0701136
Induction by low Na+ or Cl− of cocaine sensitive carrier‐mediated efflux of amines from cells transfected with the cloned human catecholamine transporters†
Authors: Pifl Christian , Agneter Ernst , Drobny Helmut , Reither Harald , Singer Ernst A 
Published: August 2006

COS‐7 cells transfected with the cDNA of the human dopamine transporter (DAT cells) or the human noradrenaline transporter (NAT cells) were loaded with [3H]‐dopamine or [3H]‐noradrenaline and superfused with buffers of different ionic composition.
In DAT cells lowering the Na+ concentration to 0, 5 or 10 mM caused an increase in 3H‐efflux. Cocaine (10 μM) or mazindol (0.3 μM) blocked the efflux at low Na+, but not at 0 Na+. Lowering the Cl− concentration to 0, 5 or 10 mM resulted in an increased efflux, which was blocked by cocaine or mazindol. Desipramine (0.1 μM) was without effect in all the conditions tested.
In NAT cells, lowering the Na+ concentration to 0, 5 or 10 mM caused an increase in 3H‐efflux, which was blocked by cocaine or mazindol. Desipramine produced a partial block, its action being stronger at 5 or 10 mM Na+ than at 0 mM Na+. Efflux induced by 0, 5 or 10 mM Cl− was completely blocked by all three uptake inhibitors.
In cross‐loading experiments, 5 mM Na+‐ or 0 Cl−‐induced efflux was much lower from [3H]‐noradrenaline‐loaded DAT, than NAT cells and was sensitive to mazindol, but not to desipramine. Efflux from [3H]‐dopamine‐loaded NAT cells elicited by 5 mM Na+ or 0 Cl− was blocked by mazindol, as well as by desipramine.
Thus, cloned catecholamine transporters display carrier‐mediated efflux of amines if challenged by lowering the extracellular Na+ or Cl−, whilst retaining their pharmacological profile. The transporters differ with regard to the ion dependence of the blockade of reverse transport by uptake inhibitors.

British Journal of Pharmacology (1997) 121, 205–212; doi:10.1038/sj.bjp.0701137
Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aorta
Authors: Plane Frances , Wigmore Sarah , Angelini Gianni D , Jeremy Jamie Y 
Published: August 2006

The potential role of copper (Cu2+) in modulating the activity of nitric oxide synthase (NOS) and guanylyl cyclase (GC) was investigated by use of diethyldithiocarbamic acid (DEDCA), a high affinity Cu2+ chelator.
DEDCA 100 μM inhibited sodium nitroprusside (SNP; 0.005–10 μM)‐evoked relaxation of rat isolated aortic rings precontracted with 3 μM phenylephrine (PE). A lower concentration of DEDCA (10 μM) did not significantly attenuate SNP‐evoked responses but did inhibit relaxation to the endothelium‐dependent dilator, A23187 (0.01–10 μM).
The presence of 100 μM Cu2+, but not 100 μM Fe2+, alone enhanced A23187‐ and SNP‐evoked relaxation of aortae precontracted with PE.
The inhibitory effect of DEDCA on SNP‐ and A23187‐induced relaxation was reversed by equimolar concentrations of Cu2+ but not Fe2+, indicating that DEDCA does not act via removal of haem‐iron from the NOS and GC complexes.
Superoxide dismutase (30 μ ml−1) was without effect on the inhibition of DEDCA relaxation induced by either SNP or A23187 in aortae precontracted with PE.
When assessed by radioimmunoassay, DEDCA inhibited SNP‐ and A23187‐stimulated cyclic GMP formation with IC50 values of 0.5 μM and 50 μM, respectively.
These data demonstrate that Cu2+ plays a role in controlling NOS and GC activity in the rat aorta.

British Journal of Pharmacology (1997) 121, 345–350; doi:10.1038/sj.bjp.0701144
Attenuation of p53 expression and Bax down‐regulation during phorbol ester mediated inhibition of apoptosis
Authors: Meßmer Udo K. , Brüne Bernhard 
Published: August 2006

Nitric oxide (NO) caused apoptotic cell death in murine RAW 264.7 macrophages. Associated with apoptotic morphology we observed p53 up‐regulation and increased Bax expression. 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), a protein kinase C (PKC) activator potently blocked NO‐induced apoptosis. To gain insights into the mechanisms involved we investigated the effect of TPA on apoptotic conveying proteins such as p53 and Bax.
TPA (100 nM) attentuated p53 up‐regulation elicited by the NO‐releasing compounds, S‐nitrosoglutathione (1 mM) and sodium nitroprusside (1 mM), and suppressed p53 protein accumulation in response to endogenously generated NO. Hence, TPA appeared to lower the steady state p53 level following its up‐regulation by NO.
Mezerein, a stage 2 tumour promoter and PKC activating agent was equally active to TPA. Moreover, two potent PKC inhibitors, staurosporine (10 nM) and Gö 6976 (50 nM), reversed the inhibitory effect of TPA. However, bisinoylmaleimide I (up to 500 nM) was ineffective.
By extending the studies, we revealed a TPA‐mediated p53 down‐regulation in response to etoposide (50 μM), mitomycin C (5 μg ml−1) and actinomycin D (2 μg ml−1).
With the notion that TPA suppressed apoptotic DNA fragmentation in p53 antisense expressing cells as well, we searched for additional inhibitory actions of TPA. As well as affecting p53, TPA elicited a rapid decline of the steady state level of Bax within 30 min.
We concluded that down‐regulation of two classical apoptotic promoting proteins contributes to the anti‐apoptotic action of mezerein and TPA.

British Journal of Pharmacology (1997) 121, 625–634; doi:10.1038/sj.bjp.0701156
Modulation by low sodium intake of glomerular response to cicletanine and atrial natriuretic factor
Authors: Kalinowski Leszek , Szczepanska‐Konkel Miroslawa , Jankowski Maciej , Angielski Stefan 
Published: August 2006

The aim of the study was to investigate whether cicletanine (CIC), as a potential inhibitor of cyclic GMP phosphodiesterase, is able to restore glomerular response to atrial natriuretic factor (ANF) in rats under conditions of diet deprived of sodium. We examined the effects of CIC on glomerular filtration rate (GFR), natriuresis and nephrogenous cyclic GMP excretion in response to ANF and the effects of both agents on intracapillary volume and cyclic GMP accumulation in isolated glomeruli of rats on normal and low sodium diets.
CIC (0.25 mg min−1 kg−1 BW) of ANF (0.5 μg min−1 BW) alone, given in pharmacological doses, increased Cin significantly in normal sodium rats, whereas the effect of each agent was blunted in low sodium diet rats. Pretreatment with CIC restored the increase in Cin in response to ANF infusion in low sodium diet rats. In rats on either diet, there were no differences in the extent of diuresis and natriuresis induced by CIC or ANF alone. In contrast to FENa, combined effects of both agents on V and UNaV in rats on normal and low sodium diets were observed.
In normal sodium diet rats, CIC 10−4 M or ANF 10−6 M alone inhibited angiotensin II 10−6 M (AII)‐induced decrease in intracapillary volume reflected by the glomerular [3H]‐inulin space (GIS). In contrast, CIC or ANF alone did not inhibit AII‐induced decrease in GIS in low sodium diet rats. Both agents given together inhibited AII‐induced decrease in GIS in low sodium diet rats.
CIC both alone and in combination with ANF increased nephrogenous cyclic GMP excretion and cyclic GMP accumulation in isolated glomeruli of rats on normal and low sodium diets. In rats on either diet, CIC abolished the difference in ANF‐stimulated increase in nephrogenous cyclic GMP excretion and cyclic GMP accumulation in glomeruli.
These results suggest that CIC and ANF alone induce relaxation of glomeruli and a resultant increase in glomerular filtration rate in normal sodium diet rats; in contrast, these effects are blunted in the low sodium diet rats. CIC restores glomerular response to ANF in low sodium diet rats, apparently involving inhibition of the cyclic GMP phosphodiesterase.

British Journal of Pharmacology (1997) 121, 635–642; doi:10.1038/sj.bjp.0701160
Characterization of endothelium‐derived relaxing factors released by bradykinin in human resistance arteries
Authors: Ohlmann P. , Martínez M. C. , Schneider F. , Stoclet J. C. , Andriantsitohaina R. 
Published: August 2006

Relaxing factors released by the endothelium and their relative contribution to the endothelium‐dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries.
BK produced an endothelium‐dependent relaxation of arteries pre‐contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 μM), produced a parallel shift to the right of the concentration‐response curve to BK with a pA2 of 7.75.
Neither the cyclo‐oxygenase inhibitor, indomethacin (10 μM) alone, the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 300 μM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 μM) alone, nor the combination of L‐NAME plus Hb affected the concentration‐response curve to BK. Conversely, the combination of indomethacin with either L‐NAME or Hb attenuated but did not abolish the BK‐induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca2+‐ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L‐NAME. Also, the presence of indomethacin plus L‐NAME produced contraction of arteries with functional endothelium.
The indomethacin plus L‐NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L‐NAME did not affect the nitric oxide donor, S‐N‐acetylpenicillamine‐induced relaxation.
The indomethacin plus L‐NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 μM), 4‐aminopyridine (100 μM), glibenclamide (10 μM), tetraethylammonium (10 mM) and charybdotoxin (50 nM).
In the presence of indomethacin plus L‐NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 μM) or by the inhibitor of cytochrome P450, SKF 525a (10 μM). Another cytochrome P450 inhibitor, clotrimazole (10 μM) which also inhibits K+ channels, inhibited the relaxation to BK.
These results show that BK induces endothelium‐dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo‐oxygenase derived prostanoid(s) and another factor (probably an endothelium‐derived hyperpolarizing factor). They indicate that nitric oxide and cyclo‐oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P‐450 pathway, in these arteries.

British Journal of Pharmacology (1997) 121, 657–664; doi:10.1038/sj.bjp.0701169
The effect of R 15.7/HO, an anti‐CD18 antibody, on the late airway response and airway hyperresponsiveness in an allergic rabbit model
Authors: El‐Hashim A. Z. , Jacques C. A. , Herd C. M. , Lee T. H. , Page C. P. 
Published: August 2006

The effects of a mouse (IgG1 fraction) anti‐CD 18 neutralizing antibody (R15.7) on allergen‐induced late airway response (LAR), airway hyperresponsiveness (AHR) and cellular recruitment were investigated in an allergic rabbit model.
Litter‐matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis (i.p.) and subsequently exposed to the allergen (i.p.) for the first 3 months of life were challenged with inhaled allergen as adult rabbits. Lung function in terms of dynamic compliance (Cdyn; ml cmH2O−1) and total lung resistance (RL; cmH2O−1 s−1) was monitored for 6 h following the allergen challenge. On day 16, separate groups of rabbits were pretreated with either control antibody (a non‐binding mouse IgG1, 1 mg kg−1, i.v.) or R15.7 (1 mg kg−1, i.v.) and 1 h later all were challenged with Alternaria tenuis and lung function monitored thereafter. Airway responsiveness to inhaled histamine was assessed by measuring RL and Cdyn 24 h before and after allergen challenge and bronchoalveolar lavage (BAL) was also performed 24 h before and after allergen challenge.
Pretreatment of rabbits with the control antibody had no effect on the LAR as measured by AUC (Cdyn, 0–6 h). However, the magnitude of the LAR following treatment with R15.7 was significantly reduced when compared to LAR demonstrated on 1st challenge (P<0.001) or to that of the control group on both challenges (P<0.01).
In control antibody pretreated rabbits allergen induced a significant 3.4 fold reduction in the PC50 response to inhaled histamine in terms of RL changes (P<0.05) and a significant 2.1 fold reduction in PC35 response to inhaled histamine in terms of Cdyn changes (P<0.05). However, in anti‐CD 18 antibody pretreated rabbits there was no significant change in responsiveness to histamine 24 h following allergen, as assessed by either RL PC50 or Cdyn PC35.
Allergen challenge induced a significant increase in eosinophil and neutrophil numbers (P<0.05) in rabbits pre‐treated with control antibody, whereas treatment with R15.7 significantly inhibited this increase in the numbers of both cell types.
This study demonstrates that the neutralization of CD‐18 molecules reduces allergen‐induced infiltration of both eosinophils and neutrophils into the airways and abolishes the accompanying LAR and AHR. These results provide evidence to support a role for CD‐18 adhesion molecules in the transmigration of inflammatory cells into airways.

British Journal of Pharmacology (1997) 121, 671–678; doi:10.1038/sj.bjp.0701176
Pharmacological characterization of endothelin‐induced rat pulmonary arterial dilatation
Authors: Higashi Tooru , Ishizaki Takeshi , Shigemori Kazuo , Yamamura Takaki , Nakai Tuguhiko 
Published: August 2006

The aim of study was to characterize endothelin (ET)‐induced vasodilatation in isolated extrapulmonary rat arteries (EPA) and in intrapulmonary arteries (IPA) preconstricted with 1 μM phenylephrine.
The ET‐3 (1 nM–100 nM)‐ and ET‐1 (10 nM–100 nM)‐induced transient vasodilatations in EPA were more potent than those in IPA. The vasodilatation induced by ET‐3 (100 nM) was larger than that induced by ET‐1 (100 nM).
Both the ETB antagonist, BQ788 (3 μM) and or endothelium denudation, but not the ETA antagonist, BQ123 (3 μM), abolished the vasodilatation induced by ET‐1 or ET‐3 (100 nM each) in EPA and in IPA. The ATP‐sensitive K+channel blocker, glibenclamide (20 μM) and the nitric oxide synthase inhibitor, NG‐monomethyl‐L‐arginine (L‐NMMA, 1 mM) suppressed the ET‐induced vasodilatation in EPA and in IPA.
We conclude that the vasodilatation induced by endothelins is markedly reduced in rat isolated IPA, and suggest that the endothelial ETB‐mediated vasodilatation varies depending on rat pulmonary arterial regions. Furthermore, ETB‐mediated vasodilatation involves activation of ATP‐sensitive K+ channels and of nitric oxide synthase in rat isolated EPA and IPA.

British Journal of Pharmacology (1997) 121, 782–786; doi:10.1038/sj.bjp.0701177
Vasodilator effects of adrenomedullin on small pulmonary arteries and veins in anaesthetized cats
Authors: Shirai Mikiyasu , Shimouchi Akito , Ikeda Soichiro , Ninomiya Ishio , Sunagawa Kenji , Kangawa Kenji , Matsuo Hisayuki 
Published: August 2006

This study was conducted to determine adrenomedullin (AM) action sites in the pulmonary vascular bed and the relation between its vasodilator effects and vascular tone. Moreover, an examination was made into whether calcitonin gene‐related peptide (CGRP) receptors mediate pulmonary vasodilatations induced by AM. To this end, we directly measured internal diameter (i.d.) changes in small pulmonary arteries and veins (100–1100 μm i.d.) by use of an X‐ray televison system on the in vivo cat lung.
Under control (resting vascular tone) conditions, AM injections into the left main pulmonary artery caused dose‐related i.d. increases in both small arteries and veins. The mean i.d. increase of the 100–1100 μm arteries (4±1, 11±2, and 17±2% with 0.01, 0.1, and 1 nmol kg−1 AM, respectively) was significantly larger than that for the veins (1±1, 5±2, and 7±2% with 0.01, 0.1 and 1 nmol kg−1 AM, respectively) whatever the injected dose of AM.
When unilobar hypoxia (5% O2) had decreased the i.d. of the 100–1100 μm arteries and veins by 16±3 and 6±3%, respectively, AM (0.1 nmol kg−1) was able to induce significantly larger i.d. increases in the arteries (28±3%) and veins (11±3%) than those under control conditions.
The AM‐induced i.d. response pattern in the serially connected pulmonary arteries was quite different from that induced by CGRP; AM caused a greater increase in smaller vessels (100–500 μm) than in larger vessels (500–1100 μm). In the case of CGRP, a greater increase was observed in the larger vessels.
CGRP8–37 (100 nmol kg−1, i.v., followed by a continuous infusion of 0.2 nmol kg−1 min−1) had no significant effect on the i.d. increase induced by AM (0.1 nmol kg−1) in any serial segments of the arteries and veins.
The results indicate that, in the cat, AM induces greater vasodilatation in small pulmonary arteries and lesser vasodilatation in small veins, the maximum dilatation being in the more peripheral arterial segment (100–500 μm). The vasodilator effect of AM was enhanced when vascular tone was elevated. The data suggest that the AM‐induced pulmonary vasodilatation is not mediated by CGRP receptors but by its own specific receptor.

British Journal of Pharmacology (1997) 121, 679–686; doi:10.1038/sj.bjp.0701178
Pharmacological evaluation of IQM‐95,333, a highly selective CCKAreceptor antagonist with anxiolytic‐like activity in animal models
Authors: Ballaz Santiago , Barber Ana , Fortuño Ana , Del Río Joaquín , Martín‐Martínez Mercedes , Gómez‐Monterrey Isabel , Herranz Rosario , González‐Muñiz Rosario , García‐López Maria‐Teresa 
Published: August 2006

The pyridopyrimidine derivative IQM‐95,333 ((4aS,5R)‐2‐benzyl‐5‐[Nα‐tert‐butoxicarbonyl)L‐tryptophyl]amino‐1,3dioxoperhydropyrido[1,2‐c]pyrimidine), a new non‐peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluatedin vitroandin vivoin comparison with typical CCKAand CCKBreceptor antagonists, such as devazepide, lorglumide, L‐365,260 and PD‐135,158.IQM‐95,333 displaced [3H]‐CCK‐8S binding to CCKAreceptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKBreceptors was negligible (IC50>10 μM). IQM‐95,333 was a more selective CCKAreceptor ligand than devazepide and other CCKAreceptor antagonists.Like devazepide, IQM‐95,333 was a more potent antagonist of CCK‐8S‐ than of CCK‐4‐induced contraction of the longitudinal muscle from guinea‐pig ileum, suggesting selective antagonism at CCKAreceptors.IQM‐95,333 and devazepide were also potent inhibitors of CCK‐8S‐stimulated amylase release from isolated pancreatic acini, a CCKAreceptor‐mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates.Low doses (50–100 μg kg−1, i.p.) of IQM‐95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK‐8S, two effects associated with stimulation of peripheral CCKAreceptors.IQM‐95,333 showed an anxiolytic‐like profile in the light/dark exploration test in mice over a wide dose range (10–5,000 μg kg−1). Typical CCKAand CCKBantagonists, devazepide and L‐365,260 respectively, were only effective within a more limited dose range.In a classical conflict paradigm for the study of anxiolytic drugs, the punished‐drinking test, IQM‐95,333, devazepide and L‐365,260 were effective within a narrow dose range. The dose‐response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses.In conclusion, IQM‐95,333 is a potent and selective CCKAreceptor antagonist bothin vitroandin vivowith an anxiolytic‐like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype.British Journal of Pharmacology(1997)121, 759–767; doi:10.1038/sj.bjp.0701186
The interaction of a new anti‐tumour drug, KAR‐2 with calmodulin
Authors: Orosz F , Vértessy B G , Salerno C , Crifo C , Capuozzo E , Ovádi J 
Published: August 2006

KAR‐2 (3′′‐(β‐chloroethyl)‐2′′,4′′‐dioxo‐3,5′′‐spiro‐oxazolidino‐4‐deacetoxy‐vinblastine) is a semisynthetic bis‐indol derivative, with high anti‐microtubular and anti‐tumour activities but with low toxicity. KAR‐2, in contrast to other biologically active bis‐indols (e.g. vinblastine), did not show anti‐calmodulin activity in vitro (enzyme kinetic, fluorescence anisotropy and immunological tests).
Direct binding studies (fluorescence resonance energy transfer, circular dichroism) provided evidence for the binding of KAR‐2 to calmodulin. The binding affinity of KAR‐2 to calmodulin (dissociation constant was about 5 μM) in the presence of Ca2+ was comparable to that of vinblastine.
KAR‐2 was able to interact with apo‐calmodulin as well; in the absence of Ca2+ the binding was of cooperative nature.
The effect of drugs on Ca2+ homeostasis in human neutrophil cells was investigated by means of a specific fluorescent probe. Trifluoperazine extensively inhibited the elevation of intracellular Ca2+ level, vinblastine did not appreciably affect it, KAR‐2 stimulated the Ca2+ influx and after a transient enhancement the Ca2+ concentration reached a new steady‐state level.
Comparison of the data obtained with KAR‐2 and bis‐indols used in chemotherapy suggests that the lack of anti‐calmodulin potency resides on the spiro‐oxazolidino portion of KAR‐2. This character of KAR‐2 manifested itself in various systems and might result in its low in vivo toxicity, established in an anti‐tumour test.