Medicinal Inorganic Chemistry - ACS Publications - American

Chapter 21

In Vivo Coordination Chemistry and Biolocalization of Bis(iigand)oxovanadium(IV) Complexes for Diabetes Treatment 1,

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Katherine Η· Thompson*, Barry D. Liboiron , Graeme R. Hanson , and Chris Orvig * Downloaded by UNIV OF SYDNEY on September 26, 2015 | http://pubs.acs.org Publication Date: August 25, 2005 | doi: 10.1021/bk-2005-0903.ch021

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Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada Centre for Magnetic Resonance, University of Queensland, St. Lucia, Queensland, Australia Current address: Department of Chemistry, Stanford University, Stanford, CA 94305-5080 1

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Many vanadyl complexes of the form VOL , where L is a monoprotic bidentate ligand, have been investigated for the treatment of diabetes mellitus. Not all such compounds are effective in counteracting diabetic symptomatology. An emerging picture of the metabolic fate of successful vanadium complexes is one of rapid de-complexation following oral administration, calling into question the role o f the ligand in determining relative potency. A model of V O L uptake, distribution and excretion is proposed that takes into account coordination, biolocalization and in vivo speciation results from recent studies. 2

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© 2005 American Chemical Society

In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

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Downloaded by UNIV OF SYDNEY on September 26, 2015 | http://pubs.acs.org Publication Date: August 25, 2005 | doi: 10.1021/bk-2005-0903.ch021

Vanadium, as sodium vanadate, was first recognized as having orally available insulin enhancing potential in the mid-1980's (1). Although earlier anecdotal reports of anti-diabetic efficacy dated to the late 1800's (reported in (2)), no formal experimental testing was carried out until after in vitro testing had demonstrated a potential biochemical role for vanadium (3,4). The first well-controlled in vivo trials were reported in 1985 (1). There, and in many subsequent trials (5), it has been shown that vanadium compounds (of both V(V) and V(IV)) tend to 'mimic' insulin in their diverse biochemical actions, stimulating or inhibiting many of the same metabolic pathways in vitro (6,7) and in experimental animals (for review see (8), and references therein). Despite a burgeoning interest in the anti-diabetic effects of vanadium species, neither the specific mechanism of action nor the metabolic fate of vanadium compounds is well understood. The term 'insulin enhancement' is used frequently as a reminder that vanadium never entirely substitutes for insulin, and, in fact, cannot function in vivo in the absence of insulin (9). Supplementation with vanadium reduces the requirement for exogenous insulin, especially in models of type 2 diabetes (9), and in that sense, 'enhances' existing insulin stores. With that understanding, we will use the term insulin mimetic agent (IMA) for the remainder of this article. Vanadium compounds are potentially unique among metal-containing compounds in their ability to alleviate diabetic symptomatology. Candidate pro drugs c ontaining a variety of other metal ions have been tried as alternates to vanadium compounds as insulin mimetic agents (IMA's), with modest success (10,11). However, in a head-to-head comparison between vanadium- and other metallo-maltol complexes (12), in the same animal model, at the same dose, with the same ligand, and by the same method of administration, only the vanadium compound was e ffective i η η ormalizing b lood g lucose 1 evels i η s treptozotocin (STZ)-diabetic rats. Not all chelated vanadium compounds are equally effective; in fact the range of efficacies observed for a wide variety of compounds includes negative rankings (13). Τ he most intensively studied, and the most commonly used as 'benchmark' compounds, the maltol and ethylmaltol complexes of vanadyl ([VO] ) ions, are now frequently incorporated in over-the-counter pharmaceutical preparations. Both bis(maltolato)oxovanadium(IV) (BMOV), and bis(ethylmaltolato)oxovanadium(IV), BEOV, are several times more potent as IMA's in diabetic rats than is the inorganic congener, V O S 0 (14). Both BEOV and V O S 0 have completed phase I human clinical trials. 2+

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R R= C H , Bis(maltolato)oxovanadium(IV), BMOV R= C H , Bis(ethylmaltolato)oxovanadium(IV), BEOV 3


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Recent evidence has shown that BEOV is mostly, if not entirely, dissociated prior to tissue uptake (15). This begs the question: how is the ligand important in determining relative therapeutic efficacy? Is the intact compound relevant to the purported mechanism of action? Proposed models of vanadium metabolism, based primarily on studies of inorganic vanadium compounds, assume interconversion between V(V) and V(IV) species in vivo (16,17). Are there distinct changes in this pathway with chelated complexes? These, and other related, questions, will be considered in this overview, with emphasis on very recent experimental findings.

Coordination Compounds of Vanadium for Insulin Enhancement 2

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Coordination complexes of [V^O] " * with a variety of ligands constitute the majority ο f ν anadium c ompounds ρ roposed as IMA's (13,14,18,19). A select few complexes have demonstrated significantly increased activity over inorganic vanadium sources (e.g. V O S 0 or [V0 ] ") through both in vivo (20) and/or in vitro (19,21,22) assays of potential biological effectiveness. 3

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Biologically effective V O L complexes have been synthesized with various ligands, many of which do not appear to have much in common chemically (Scheme 1). Maltol and ethylmaltol have the advantage of being approved food additives in the U.S.A., U.K. and Canada (11,23). Picolinic acid is a natural metabolite of tryptophan (24,25). Isomaltol is a structural isomer of maltol that occurs naturally in roasted coffee (26). Metformin is used worldwide as an oral hypoglycemic agent for treatment of type 2 diabetes, alone, or in combination with sulfonylureas (27). Thiazolidinediones are also commonly prescribed antidiabetic compounds (27); conjugation of kojic acid to the active portion of a thiazolidinedione molecule was used to create the bifunctional ligand, 5-[4-(52


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hydroxy-4-oxo-4H-pyran-2ylmethoxy)benzylidene]-thiazolidene-2,4-dione (Scheme 1) (28). A l l of these ligands, when complexed in a 2:1 ratio with [V O] , formed effective IMA's with remarkably similar glucose-lowering responses when tested in a standard acute testing protocol (13,20,24,28,29). In other words, at the E D dose for BMOV (0,12 mmol kg" i.p. or 0.55 mmol kg" by oral gavage), V O L compounds, where L is one of the ligands shown in Scheme 1, were equivalently effective at 12, 24 and 48 h after administration in normalizing blood glucose in STZ-diabetic rats. ,v

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2

ΛΛ NH

H N 2

R « C H , maltol R = C H , ethytmaltol R-1-C3H7, isopropylmaltol 3

2

NH

Ν Η

Ν—CH J CH

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W,/V'-diniethylbigijanide, metformin 5-(4-(5~hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzylidene]-thiazolidene-2,4-dione

r

[|

Ο

Ν OH

Pyridin e-2carboxylic acid

isomaltol

Scheme L Ligands that have been incorporated into bis(ligand)oxovanadium(LV) complexes (VOL^ showing similar effectiveness as IMA's in the same in vivo acute testing protocol in STZ-diabetic rats.

V(III) complexes of some of these same ligands have also been synthesized and characterized (30,31). On average, V L complexes were less efficacious in counteracting the hyperglycemia of STZ-induced diabetes in rats (13). Complicated oxidation processes to V(IV) and V(V) occur rapidly under physiological conditions (30). m

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V(V)-containing complexes have also been proposed as IMA's (19,32). The coordination chemistry of vanadium(V) and vanadium(IV) usually involves oxygen-rich ligands, but nitrogen- and sulfur-bonding are also well-represented


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(19,33). Indeed, vanadium(V) has a particularly varied coordination chemistry. Non-rigid stereochemical requirements for V(V) permit coordination geometries from tetrahedral and octahedral to trigonal- and pentagonal-bipyramidal. The higher poordinative flexibility of vanadate compared to phosphate has, in fact, been used to advantage for structural characterization of phosphatase enzymes (34). Unlike phosphate, vanadate is readily reduced in vivo (to vanadyl). The vanadyl ion does not serve as a phosphate analog, but instead competes preferentially with other divalent cations (35,36).

Coordination and Speciation in Vivo In aqueous solution, under physiologically relevant conditions, V O L may be subject to oxidation, dissociation and ligand substitution effects. The second order rate constant for the oxidation of BMOV by 0 (pH = 7.25, T= 25°C) is 0.21 M* sec" (37), with a known temperature dependence suggesting that at 37°C, the rate would be severalfold faster. The oxidation product, [V0 (ma) ]\ can readily interact with ascorbate, and secondarily, with glutathione (38). 2

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The biological milieu typically includes a large number of potentially competing ligands (39). Speciation studies of inorganic vanadium compounds (40) suggest rapid binding in the bloodstream to transferrin primarily, and to albumin, citrate, and smaller organic ligands to a lesser degree. Kiss et al (41), studying ligand substitution effects on BMOV, concluded that "in the absence of specific kinetic effects maltol can readily be replaced by a stronger ligand and V 0 can rapidly form thermodynamically [more] stable complexes in ligand rich environments such as biological fluids." A modeling study (39) of chelated vanadium binding to both low molecular mass (oxalic acid, citric acid, lactic acid and phosphate) and high molecular mass (albumin and transferrin) binders predicted that -70% of V supplied as VOL , especially as BMOV, or bis(picolinato)oxovanadium(IV) (VO(pic) ), would be bound to transferrin in the circulation and the remaining -30% bound to low molecular mass binders, especially citrate. This result was subsequently confirmed empirically in speciation studies by pH potentiometry (42). An initial EPR spectroscopic investigation of BMOV binding to transferrin confirmed that complexation would readily take place at ambient temperature (43), and recently, a thorough variable temperature EPR study of BMOV binding to transferrin and other serum proteins showed unequivocally that BMOV binds to transferrin in a manner indistinguishable from that of VOS0 (44) (Figure 1). 2 +

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Intact Compound vs. Dissociated Metal Ion: Which Is It? The evidence for dissociation of V O L in vivo includes several seminal studies. As noted above, coordination ο f ν anadyl t ο h uman s erum t ransferrin was shown to be the same, regardless of whether V O S 0 or BMOV is combined with apo-transferrin (Fig. 1) (44,45). Vanadium, whether from chelated or unchelated sources, appears to accumulate preferentially in bone (46-48). Coordination binding of V 0 derived from BEOV given in the drinking water was identical to that seen for VOS0 -fed rats, in both kidney and bone (49). Detailed ESEEM analysis of vanadyl binding to a triphosphate model system (50) demonstrated the feasibility of vanadyl coordination to phosphates on the bone mineral surface, rather than incorporation into the apatitic lattice. 2

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2.4

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2.2

2.1

2.0

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g-factor Figure 1. EPR spectra of (top) apo-transferrin, 0.29 mM, vanadyl sulfate, 1.11 mM; (middle) apo-transferrin, 0.13 mM, BMOV, 0.11 mM; and (bottom) BMOV, 1.10mM(T=298K,pH7.4, 0.16MNaCl).


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In the kidney, vanadyl ions appear equatorially coordinated to amine nitrogen atoms, whether the vanadyl originatedfromV O S 0 (51) or from BEOV (49), resulting in EPR spectra that are entirely congruent. By contrast, V 0 from bis(picolinato)oxovanadium(IV), VO(pic) (52,53) in kidney and liver was seen to bind principally to amine nitrogens, but secondarily to imine (pyridyl) nitrogens, suggesting a possible residual fraction of the dose as undissociated VO(pic) (52); thus, the likelihood of residual intact VO(pic) in kidney tissue was considerably higher than for residual intact BEOV. However, the principal reason for this discrepancy is an experimental limitation: Ο ^-coordination (which would be anticipated from BEOV) does not result in an observable ESEEM pattern. The appearance of both amine and imine binding following i.p. chelated vanadyl demonstrates that at least a major portion of the chelated vanadyl compound undergoes ligand dissociation and substitution even in the absence of absorptive and/or digestive processes (44). 4

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At the cellular level, vanadium from BMOV may be incorporated into phosphotyrosine phosphatases as [V0 ] " (Figure 2) (54). Insofar as the mechanism of action of vanadium IMA's purports to involve phosphotyrosine phosphatase inhibition, the appearance of vanadate alone in the active site of PTP1B incubated in vitro with BMOV (Figure 2) further supports the mounting evidence that vanadium must be released from the compound in order for it to be pharmacologically active (54). 3

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Perhaps most convincing are the pharmacokinetics of disappearance of vanadium, which differed substantially from those of C from an oral dose of [ethyl-l- C]BEOV (Figure 3); the tissue uptake was entirely different for the radiolabelled ligand and for vanadium (15). Instead of the ligand being present at roughly twice the concentration of vanadium in the blood (as would be anticipated from VOL ), it is present at a lower concentration compared to vanadium from the 1-hour timepoint onwards. Modeling predictions of pharmacokinetic parameters, such as half-life and time of maximal concentration, were also entirely dissimilar for a broad range of tissues studied (liver, kidney, bone, small intestine and lung) (15). l 4

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Thus, a number of recent studies have demonstrated fairly conclusively that vanadium IMA's dissociate rapidly once ingested or injected. Elucidation of the coordination environment (43,44,47) and probable speciation (38,41,42) of vanadium compounds in vivo suggests an eventual metabolic fate for chelated vanadium complexes that differs little, if any, from that of non-complexed vanadium compounds, when the compounds are administered orally.



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Figure 2. Crystal structure ofPTPlB (C215S mutant) soaked with BMOV reveals [VO4] " coordinated to serine 215 in a trigonal bipyramidal geometry. (A) Stereoview of the difference electron density in the active site ofPTP1B, shown together with thefinalmodel of the oxovanadate ligand. Most protein atoms are omitted for clarity. Axial vanadium-oxygen bonds are shown as thick broken lines, select hydrogen bonds between ligand and enzyme are shown as thin broken lines. (B) Detailed representation of the Η bonding network of [VO4] ' with backbone atoms in the PTP1B (C215S mutant) active site. (54). Reprintedfrom J. Inorg. Biochem. 96, Peters etal. "Mechanism of insulin sensitization by BMOV (bis maltolato vanadium); unliganded vanadium (VO4) as the active component, "pp. 321-330, 2003, with permissionfromElsevier. 3

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Oral Bioavailability If V O L indeed dissociates rapidly after ingestion, then the differential efficacy between V O S 0 and VOL must be due to very early effects on bioavailability, either at the level of absorption, or shortly thereafter. Bioavailability of a metallopharmaceutical is defined as "the amount of a dose that is functionally usable by an organism" (55). Relative efficacy of vanadiumcontaining therapeutic agents, analogous to other small molecule metalcontaining therapeutics, may not be due solely, or even mostly, to the presence of intact compound in the circulation. 2

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Figure 3. Blood [V] and C concentrations after a single bolus dose offethyll- C]BEOV (50 mg kg' in 2mL 1% carboxymethylcellulose, n = 4 rats for each time point). Data are expressed as means ±SEM (15). l4

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An emerging picture of V O L metabolism (Scheme 2) is thus not substantially different from that of inorganic vanadium compounds. For BEOV (and presumably also BMOV), dissociation of at least a major portion of the dose occurs within an hour of ingestion. VOL , including BMOV, VO(pic) and bis(iodopicolinato)oxovanadium(IV), VO(IPA) , are cleared rapidly (less than 0.5 h) from the circulation (46,56,57). 2

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Once out of the systemic circulation, vanadium is clearly taken up by many different tissues (46,58,59). Vanadium, whether administered as a vanadium(IV) or vanadium (V) salt, e.g. VOS0 or [ V 0 ] \ respectively, accumulates predominately in bone, liver and kidney tissue (59-62). (Because vanadate ([V0 ] ') has various protonation states under physiological conditions, we use Vj to denote all protonation states, V = [V0 ] ' / [HV0 ] " / [H V0 ]".) Binding of V(IV) and/or V(V) to fiber in the lower GI tract and to ferritin in the liver, and conjugation prior to urinary excretion, are unchanged from models appropriate to inorganic vanadium compounds (16,17). Miscellaneous losses in hair, skin and nails (63) are presumed to account for significant decreases in overall body burden over time (64). 3


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{

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Distributions from chelated vanadium sources, e.g. BMOV (46) and vanadyl picolinate (48) show a similar profile. Both the amount and relative vanadium concentrations in these organs vary with the particular compound and dose, but the percentage of dose taken up (whether from an oral or an i.p. dose) is generally significantly higher from chelated sources (46,48) compared to that from inorganic vanadyl compounds (56,59,61,65). Thus, chelation improves bioavailability, reducing the dose required for therapeutic effect (55). A dose adjustment is necessary when administering V O L by i.p. injection, as opposed to V O L by oral ingestion (whether in the drinking water or by oral gavage) (Scheme 2). Dose adjustment was empirically determined to be roughly a factor of five lower for i.p. administration (9), implying a gastrointestinal absorption of 20%. This result is consistent with compartmental modeling predictions (46). 2

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Improved bioavailability οf some V O L compared to thatof V O S 0 may involve not only improved uptake into the circulation, but also delayed release from the bloodstream (and consequent tissue uptake). In a recent study comparing V(IV) clearance from the bloodstream following several different V O L administered i.p., delayed clearance of the compound from the systemic circulation appears to correlate with improved pharmacological potency (53,66). This mechanism for increased potency would fit well with the proposed formation of a ternary complex between some V O L (e.g. BMOV and 2

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394 bis(acetylacetonato)oxovanadium(IV) (VO(acac) (67)) and human serum albumin, observed by EPR spectroscopy (43,44). Albumin binding to metallopharmaceuticals has been shown previously to effectively delay circulatory clearance, facilitating appropriate tissue targetting (68).


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Scheme 2. Schematic outline ofVOL metabolism (adaptedfrom 16,64 2

The lack of efficacy of some V O L could then be due to either high lability, in which case the dissociated compound behaves exactly like V O S 0 in the biological milieu, or to tight coordination, in which case V 0 is never released, and the compound may be absorbed even more poorly than is VOS0 . Ideally, the ligand remains bound to the metal ion long enough to delay oxidation and/or favor binding to albumin, with consequent ternary complex formation (43,44) and prevention of gastrointestinal irritation (69). 2

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The proposed vanadium delivery to tissues by V O L (Scheme 2) is not unlike that of a number of other biologically relevant metal ions, e.g. copper and manganese, which are both essential and toxic (55,70). A well-studied example is the tissue uptake of ferric maltol, developed specifically to lessen the gastrointestinal irritation associated with ferrous compounds in treating iron deficiency (23). Rather than diffusing across the intestinal wall, dissociating immediately, and allowing Fe binding to transferrin, the ferric ion appears to be first reduced, then donated to an endogenous uptake carrier, and thus remains under regulatory control. Saturable uptake kinetics for radiolabelled iron entry from ferric maltol are evidence of this unproved pathway for delivery of iron to intestinal cell surface carriers (23). 2


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A similar process of uptake, distribution and metabolism may be operative for chromium picolinate, (Cr(pic) ). In a study in which Cr or H-labelled complex was administered intravenously (i.V.), metabolic fates of the metal ion and the ligand were compared (71). Cr(pic) was clearly dissociated prior to urinary elimination of Cr; size exclusion chromatography indicated that the chromium-containing fraction had a molecular weight of -1500. Blood chromium concentrations were similar at both 4 and 24 h after consuming a diet containing either CrCl or Cr(pic) ; tissue concentrations were, on the other hand, four to five times higher following Cr(pic) oral administration (71). Although CrCl is readily taken up by apo-transferrin (72), Cr(pic) may not be so readily bound, and hence may be bound preferentially by albumin, with consequent slower clearance from the bloodstream. Decomposition of Cr(pic) , as well as Cr(III) propionate, has been studied under physiologically relevant conditions (neutral aqueous solutions, and in artificial gastric juice, pH -2) (73) by UV-Visible spectroscopy, electrospray mass spectrometry and X-ray absorption spectroscopy. Although ligand exchange for Cr(III) complexes is relatively slow compared to that of vanadyl complexes (on the order of several hours) (74), the dissociation process is nonetheless biologically significant. 5I

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Whether administered as V(III), V(IV) or V(V), vanadium in vivo speciation is dominated by interconversion between V(IV) and V(V) (38), which would presumably underlie the biolocalization of any of the chelated vanadium complexes. Amine- (and possibly also imine) binding in kidneys, phosphatebinding and adsorption on the bone, and potential ternary complex formation in the circulation are all specific to particular VOL , according to evidence gathered so far, but may have more general application to chelated vanadium compounds. 2


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Summary and Conclusions Ensuring delivery of the vanadium ion to the site of incorporation appears to be the main role of the ligand in VOL . Prior to this incorporation, the metal ion must be prevented from incurring toxicity through gastrointestinal irritation, then chaperoned through the systemic circulation such that overly rapid clearance is avoided, and finally sequestered in tissues well-equipped to maintain the vanadium in storage for release and utilization as needed. A major role of the complexation of vanadium ions may, in fact, be in slowing down both the uptake into and release of vanadium from the circulation. Downloaded by UNIV OF SYDNEY on September 26, 2015 | http://pubs.acs.org Publication Date: August 25, 2005 | doi: 10.1021/bk-2005-0903.ch021

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Acknowledgement The authors gratefully acknowledge past co-workers (cited below) and financial support from the Canadian Institutes of Health Research (operating grants), the Natural Sciences and Engineering Research Council (fellowships and operating grants), the Science Council of British Columbia (B.D.L., GREAT program), and an Australian Research Council International Research Exchange (IREX) program grant to G.R.H. and C O . We thank Prof. John McNeill and his group, as well as Kinetek Pharmaceuticals, Inc., for long-term, fruitful collaboration.

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