New Lead for Pain Treatment

RESEARCH NEWS & VIEWS

MEDICINAL CHEMISTRY bridgehead positions. In devising a strategy to prepare this system, the authors turned to nature for inspiration. Conolidine is a ‘C5-nor stemmadenine’ New lead for natural product, which means that it con tains the same carbon skeleton as the more abundant natural product stemmadenine, pain treatment except that it lacks one of the carbon atoms (known as C5; see Fig. 1b). It has been pro The synthesis of conolidine, a scarce, naturally occurring compound, has enabled posed3 that, in the biosynthesis of C5-nor the first studies of its pharmacological properties to be carried out. Excitingly, stemmadenine compounds, the C5 atom of conolidine is a painkiller that seems to have an unusual mechanism of action. a stemmadenine framework is excised in a process that begins with the oxidation of the bridgehead nitrogen (Fig. 1c). This proposal SARAH E. REISMAN et al.1), might pave the way for the development has been validated chemically — stemm of new non-opioid analgesics. adenine can be converted to its C5-nor ome of the most powerful painkillers, The natural product conolidine was origi analogue vallesamine in this manner, albeit in such as morphine, hydrocodone and nally isolated2 in extremely small quantities low (25%) yield4. oxycodone, belong to the opioid family — just 0.00014% yield — from the stem bark Rather than pursuing a strictly biomimetic Sof analgesics. Unfortunately, prolonged expo of the flowering tropical plant Tabernaemon- sequence in which a compound containing the sure to these analgesics can cause several tana divaricata. The low natural abundance stemmadenine framework was converted to adverse side effects, including physical and of the compound has hindered the study of conolidine, Micalizio and the chemistry team1 psychological addiction. As a result, there its potential therapeutic properties. By com adopted a more subtle approach. They devel is a continued effort to identify painkillers pleting the first total chemical synthesis of oped a short synthesis of a compound that has that have different biological mechanisms conolidine, Micalizio and co-workers provided all but one of the carbons found in conolidine from opioids and that elicit fewer side effects. Bohn’s team with enough synthetic material to (Fig. 1d). They then incorporated the final With this in mind, a team of chemists, led carry out the first in vivo studies of its analgesic carbon by reacting the compound with formal by Glenn Micalizio, has joined forces with a properties. dehyde (CH2O), generating a precursor similar group of neuroscientists, headed by Laura A key challenge in the synthesis of cono to that produced in the biomimetic synthesis Bohn, to synthesize and study the analgesic lidine is the construction of its bicyclic ring of vallesamine. This precursor then underwent properties of a rare, naturally occurring com system (Fig. 1a), which consists of an eight- an intramolecular cyclization reaction to forge pound called conolidine. Their promising find membered ring bridged by two carbon atoms the critical eight-membered ring of the bicyclic ings, reported in Nature Chemistry (Tarselli and contains a nitrogen atom at one of the system. This approach enabled the team to prepare conolidine in a more straightforward manner than would have been possible by first making C5 the stemmadenine framework and then frag a b N N menting it. In addition, using this approach,

H N H they were able to independently prepare not O H MeO2C HN Me Me HO only the naturally occurring isomer of cono Conolidine Stemmadenine lidine, but also its unnatural mirror-image isomer (known as (–)-conolidine), in only ten c Bond breaks synthetic steps from a commercially available OH Loss of starting material. N N Oxidation + H2C O H N Stemmadenine With access to synthetic conolidine, Bohn 1 H H H N MeO2C HN MeO2C N MeO C and her group went on to evaluate the com Me Me 2 H HO HO Me HO pound’s analgesic properties in mice. In Cyclization precursor Vallesamine experiments designed to evaluate conolidine’s effects on both acute and persistent pain, d CH2 they found that it was indeed a painkiller of NH Acid N N + similar potency to morphine. However, the H O N H2C H N H N O H O H O authors’ pharmacological studies revealed that Me Me Me H Cyclization precursor Conolidine conolidine does not bind to opioid receptors (the biological targets responsible for the analgesic effects of morphine and other opi oid drugs). Furthermore, the authors found Figure 1 | Inspiration for the synthesis of conolidine. a, Conolidine is a scarce, plant-derived that conolidine does not seem to adversely compound. Its core structure is shown in blue. Me is a methyl group. b, Stemmadenine is a related affect the locomotor activity of mice, as opioid natural product. Its core structure (red) has one more carbon atom than conolidine; the carbon atom is analgesics do, suggesting that conolidine might known as C5. c, The biosyntheses of compounds containing the core structure of conolidine are thought have fewer side effects than opioids. to involve a process in which the C5 carbon is excised from the stemmadenine core. In this example, Intriguingly, Bohn and colleagues also the oxidation of a nitrogen atom in stemmadenine triggers the loss of C5 as formaldehyde (CH2O) and generates a cyclization precursor, which undergoes an intramolecular reaction to yield vallesamine as a observed that (–)-conolidine has compara product. Curly arrows show the electron movement in the intramolecular reaction. d, In their synthesis ble in vivo activities to (+)-conolidine, the of conolidine, Tarselli et al.1 prepared a compound that, on treatment with an acid and formaldehyde, naturally occurring isomer. This is unusual, formed a cyclization precursor similar to that shown in c. The precursor underwent an intramolecular because the two mirror-image isomers (enan reaction that formed the desired product. tiomers) of a compound commonly elicit

458 | NATURE | VOL 473 | 26 MAY 2011 © 2011 Macmillan Publishers Limited. All rights reserved NEWS & VIEWS RESEARCH different biological responses. For example, the indicate that conolidine is a promising candi California Institute of Technology, Pasadena, enantiomer of morphine is a poor painkiller5. date for further study as a non-opioid analge California 91125, USA. The fact that both enantiomers of conolidine sic. Moreover, the authors’ concise, modular e-mail: [email protected] are analgesic may indicate something about its and high-yielding chemical synthesis should 1. Tarselli, M. A. et al. Nature Chem. 3, 449–453 biological target. Taken together, the biologi provide ample quantities of conolidine for the (2011). cal findings suggest that conolidine may have further study and development of this pain 2. Kam, T.-S., Pang, H.-S., Choo, Y.-M. & Komiyama, K. a previously undiscovered pharmacological killer — quantities that would be extremely Chem. Biodiver. 1, 646–656 (2004). 3. Potier, P. & Janot, M. M. C.R. Acad. Sci. 276C, 1727 mechanism for inducing analgesia. difficult to extract from the natural source of (1973). Just what the mechanism of action is has not the compound. ■ 4. Scott, A. I., Yeh, C.-L. & Greenslade, D. J. Chem. Soc. been determined, and this is clearly a prior Chem. Commun. 947–948 (1978). 5. Rice, K. C. in The Chemistry and Biology of ity for future research. Micalizio, Bohn and Sarah E. Reisman is in the Division of Isoquinoline Alkaloids (eds Phillipson, J. D., Roberts, colleagues’ preliminary studies1 nevertheless Chemistry and Chemical Engineering, M. F. & Zenk, M. H.) 191–203 (Springer, 1985).

PRECISION MEASUREMENT monofluoride (YbF), to surpass the measure ment sensitivity achieved in the thallium-based experiment3 — albeit, at present, by a mod est factor of 1.5. Specifically, the authors limit A search for electrons the magnitude of the electron’s electric dipole moment to less than 10.5 × 10−28 e centimetres, where e is the charge of the electron. In electro that do the twist static units, this value is more than 16 orders of magnitude weaker than the known mag One might think that physicists know everything about the electron. But the netic dipole moment of the electron. Hudson latest measurement of its shape could alter expectations for results at high-energy and colleagues have pioneered the use of particle accelerators. See Letter p.493 cold polar molecules to push the search for an electric dipole moment of the electron to new levels, and their work serves as a gateway AARON E. LEANHARDT negative terminals, and its orientation can be to multiple next-generation molecule-based rotated by electric fields. Therefore, the experi experiments. These experiments6–10, as well f I were to tell you about an elementary mental effort of Hudson and colleagues can be as a continued effort by Hudson et al.1, are aim particle that has mass and charge, but viewed as an attempt to answer the question: ing to improve on the above-mentioned limit neither size nor structure, yet still has a does an electric field twist the orientation of by a factor of 10–100. Iwell-defined orientation and can point in a an electron? How can studying a sizeless and struc specific direction in space, you would prob It should be expected that stronger electric tureless particle be so interesting? The inter ably think I am describing something from a fields and longer measurement times would est arises from its interaction with another science-fiction novel. In fact, I am telling you enhance the probability of observing the elec seemingly featureless entity — empty space, about the electron. On page 493 of this issue, tron ‘doing the twist’. Herein lies the difficulty. casually called the vacuum. In reality, empty Hudson et al.1 describe an experiment aimed A free electron will accelerate under the influ space is not always so empty. The vacuum at refining our understanding of this funda ence of an electric field and crash into the walls comprises a sea of particles that are hopping mental particle and, more broadly, the basic of the apparatus. This effect is extremely useful into and out of existence like waves crash laws of nature. for generating X-rays in medical devices and ing onto a shore and then receding back to Described colloquially, their experiment security scanners, but in the present experi the ocean. These whimsical particles do not searches for evidence of an aspheric distor ment it has only the detrimental effect of stick around for long enough to be observed tion to the shape of the electron, or, more limiting the measurement time. This obstacle directly. However, they make their presence technically, to the shape of its interactions with can be overcome by binding several electrons felt through their interaction with common electric fields. Hudson et al.1 observe no such to a heavy nucleus to form a neutral atom com place matter, such as the electrons studied by distortion. However, a detailed understanding prising a central core and some outer valence Hudson and colleagues1. of their apparatus allows them to report their electrons. An electric field will not accelerate Physicists contend that it is these particles null result as a new limit on the magnitude of this neutral atom, but will polarize it — that that give the electron its electric dipole the electric dipole moment of the electron. is, it will separate opposite charges within the moment, almost as if they are the band playing This work has important ramifications for atom. Furthermore, the effective electric field just the right music required for the electrons the types of particles that can be discovered ‘seen’ by the valence electrons in a suitably to do the twist. Without these particles, no at high-energy accelerators, and may even chosen and properly polarized neutral atom electric field would be strong enough and tually help to explain the composition of the can be quite large2. The previous best attempt no measurement time long enough for us to observable Universe. to detect the electric dipole moment of the see the electrons dance. Furthermore, they It is well established that the electron has a electron was made by probing the valence are a subset of the new particles that physicists magnetic dipole moment, which means that electrons in a beam of neutral thallium atoms3. working at high-energy accelerators are hoping it behaves like a tiny bar magnet with north Even before the thallium-based experiment3 to create and observe directly. Hence, searches and south poles. For example, a magnetic field was completed, techniques to improve on it for the electric dipole moment of the electron can rotate the orientation of an electron, just as were being devised. Molecules are typically provide crucial information about phenom it can move the needle of a compass. Hudson easier to polarize than atoms, which trans ena that naturally occur at energies 1030 times et al.1 are searching for the as-yet undiscovered lates into the molecular valence electrons greater than those directly measured in the electric analogue, the electric dipole moment experiencing even larger effective electric precision tabletop work of Hudson et al.1. of the electron. An electric dipole moment fields4,5. This benefit was crucial in enabling In 1950, common theoretical arguments can be depicted as a battery with positive and Hudson et al.1, who worked with ytterbium asserted that fundamental particles could not