Convergent synthesis and pharmacology of substituted tetrazolyl-2-amino-3- (3-hydroxy-5-methyl-4-isoxazolyl)propionic acid analogues

Article abstract of DOI:10.1021/jm050014l

The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (AS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5- tetrazolyl)-4-isoxazolyl]propionicacid(2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure-activity relationship are provided.

Full text of DOI:10.1021/jm050014l

3438
J. Med. Chem. 2005, 48, 3438-3442
Convergent Synthesis and Pharmacology of Substituted
Tetrazolyl-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid Analogues
Stine B. Vogensen,† Rasmus P. Clausen,† Jeremy R. Greenwood,† Tommy N. Johansen,† Darryl S. Pickering,‡
Birgitte Nielsen,† Bjarke Ebert,§ and Povl Krogsgaard-Larsen*,†
Department of Medicinal Chemistry and Department of Pharmacology, The Danish University of Pharmaceutical Sciences,
2 Universitetsparken, DK-2100 Copenhagen, Denmark, and Department of Electrophysiology, H. Lundbeck A/S,
9 Ottiliavej, DK-2500 Valby, Denmark
Received January 7, 2005
The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of
(RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-
AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter
and more convergent synthetic route than previously described, employing a new method for
introducing the amino acid moiety, was developed for these derivatives. The 2-substituted
isomers were selective agonists, and their activity correlated inversely with the size of the
substituent. Structural explanations of the structure-activity relationship are provided.
Introduction
(S)-Glutamic acid (Glu) is the major excitatory neuro-
transmitter in the central nervous system (CNS). The
effects of Glu are mediated by ligand-gated ionotropic
receptors (iGluRs) and G-protein-coupled metabotropic
receptors (mGluRs). It is generally agreed that GluRs
are implicated in a variety of CNS functions, including
learning and memory, and that GluRs are potential
therapeutic targets in a number of neurological and
psychiatric disorders.1,2 The iGluRs are categorized into
three classes according to selective activation by the
agonists N-methyl-D-aspartic acid (NMDA), (S)-2-
amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid
[(S)-AMPA, 1] (Figure 1), and kainic acid (KA). Func-
tional iGluRs are believed to assemble as tetramers
from homo- or heteromeric combinations of a number
of different subunits.1,3 Thus, seven NMDA subunits
(NR1, NR2A-D, NR3A,B), four AMPA subunits (GluR1-
4), and five KA subunits (GluR5-7, KA1,2) have been
cloned and characterized. In recent years, X-ray crystal-
Figure 1. Chemical structures of (S)-glutamic acid (Glu),
(S)-AMPA [(S)-1], and the AMPA agonist (S)-(2)-Me-Tet-AMPA
[(S)-2], 1-Me-Tet-AMPA (3) and structures of the new series
of alkylated tetrazolyl analogues of AMPA (4a-c, 5a-c).
lographic studies of soluble constructs of the S1S2
ligand-binding domain of GluR2, cocrystallized with
agonists and antagonists, have provided detailed in-
sights into the processes of receptor activation, modula-
tion, and inhibition.4-8
Xenopus laevis oocytes consisting of AMPA receptor
subunits (GluR1-4), (S)-2 displayed a minor subunit
selectivity, showing some preference for cloned homo-
meric GluR3 or GluR4 receptors over heteromeric
GluR1/GluR2 or homomeric GluR2 receptors.10 More
recently, (S)-2-Me-Tet-AMPA was cocrystallized with
the GluR2S1S2 construct, and it was shown that the
2-methyltetrazolyl substituent is accommodated by a
partly hydrophobic pocket in the ligand-binding domain.
Interestingly however, the tetrazole ring was not in-
volved in hydrogen bonding, save for a long intra-
molecular contact, but it merely filled out the pocket.6
To further investigate the structural requirements of
the AMPA receptor for agonist binding, we then initi-
ated and now describe the synthesis and pharmacologi-
Enantiomeric resolution and pharmacological char-
acterization of (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-
2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-
AMPA, (RS)-2) has previously revealed (S)-2 as the most
potent AMPA receptor agonist yet described,9,10 whereas
the isomeric 1-Me-Tet-AMPA (3) shows no significant
pharmacological activity.9 In electrophysiological experi-
ments using cloned homo- or heteromeric receptors in
* To whom correspondence should be addressed. Phone:
+45 35306511. Fax: +45 35306040. E-mail: ano@carlsbergfondet.dk.
† Department of Medicinal Chemistry, The Danish University of
Pharmaceutical Sciences.
‡ Department of Pharmacology, The Danish University of Pharma-
ceutical Sciences.
§ H. Lundbeck A/S.
10.1021/jm050014l CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/08/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3439
Scheme 1a
Scheme 2a
a Reagents and conditions: (a) BrCH(CH3)2, K2CO3, DMF,
60 °C; (b) aqueous NH3, room temp; (c) POCl3, 70 °C; (d) NaN3,
Et3NHCl, DME, reflux; (e) ICH2CH3, K2CO3, acetone, room temp;
(f) n-BuLi, (CH2O)3, THF, -78 to 20 °C; (g) SOCl2, reflux;
(h) AcNHCH(CO2CH3)2, NaH, NaI, DMF, room temp; (i) 6 M
HCl/AcOH, reflux.
cal characterization of a series of substituted tetrazolyl-
AMPA analogues in which the methyl group is replaced
by ethyl (4a, 5a), propyl (4b, 5b), or isopropyl (4c, 5c)
substituents.
Results
a Reagents and conditions: (a) n-BuLi, -78 °C, THF, I2;
(b) n-BuLi, -78 °C, THF, 17, -50 to -40 °C; (c) NaN3, Et3NHCl,
DME, 90 °C; (d) 6 M HCl, room temp. (e) a and b: RI, K2CO3,
acetone, room temp. (e) c: 23, toluene, reflux. (f) 48% aqueous
HBr, reflux.
Chemistry. For the synthesis of the target tetrazolyl
analogues of AMPA, a more convenient route than that
employed in the original synthesis of 2-Me-Tet-AMPA9
was developed. The 2-ethyl-substituted 5a was synthe-
sized following the strategy outlined in Scheme 1. The
3-isoxazolol 6 obtained from dimethyl acetylenedi-
carboxylate11 was protected as the O-isopropyl ether 7.
Aminolysis of the ester 7 to amide 8 was followed by
dehydration to nitrile 9. The reaction of 9 with in situ
generated hydrazoic acid afforded tetrazole 10. Subse-
quent alkylation with ethyl iodide gave the regioisomers
11 and 12 (ratio 1:3), which were separated by laborious
flash column chromatography. Metalation of 12 followed
by reaction with trioxane led to the alcohol 13, albeit
in low yield, which was converted to 14 with thionyl
chloride. Reaction of chloromethyl 14 with dimethyl
acetamidomalonate in the presence of sodium iodide
provided 15, which upon acidic deprotection gave 5a.
In light of the inconvenience of the route outlined in
Scheme 1, there obviously was room for improvement
of the synthetic strategy (Scheme 2). Surprisingly,
lithiation of the 4-position of the isoxazole ring of 9 at
-78 °C was possible without affecting the nitrile group,
and the lithium salt in THF solution was stable for
several hours at -20 °C. Reaction of the lithiated species
with iodine gave 16 in 68% yield (Scheme 2). This
observation opens up the possibility of introducing the
amino acid moiety at an early stage in the synthesis,
but because of the sensitivity of 9 toward hydrolysis,
traditional strategies involving Strecker or Ugi synthe-
ses did not seem feasible. Instead, a Michael addition
of 9 to an R-amino acrylate was considered. Various
acrylates were tried, and amino acrylate 1712 afforded
18 in 45% yield. Employing other metals such as Cu
and Mg in this reaction did not improve the yield.
Treatment of 18 with sodium azide and triethylamine
hydrochloride gave tetrazole 19 as a key intermediate.
Selective deprotection using hydrochloric acid led to
amino acid 20 in quantitative yield. Alkylation of 19
with ethyl iodide gave 21a and 22a in a 1:2 ratio.
Similarly, alkylation with propyl iodide gave the regioi-
somers 21b and 22b in a 1:4 ratio. Alkylation of 19 with
isopropyl bromide was very slow, whereas alkylation
using O-isopropyl-S-propargyl xanthate 2313 provided
the two regioisomers 21c and 22c in a 1:2 ratio. In
agreement with the literature14 2-alkylation of the
tetrazole 19 was favored over 1-alkylation because of
steric effects. The regioisomers were separated using
flash chromatography. Deprotection of 21a-c and 22a-c
in one step led to the target products 4a-c and 5a-c,
respectively. The regioisomeric assignment was based
on a comparison of the tetrazole 13C signal in regioi-
somers 21a-c and 22a-c. Thus, the tetrazole carbon

3440 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Brief Articles
Table 1. Receptor Binding Affinities and Electrophysiological
believed to reflect the agonized state of the receptor. The
X-ray structure of (S)-2 bound to GluR2S1S2J (1M5B)6
was prepared for docking according to the method
recommended in the First Discovery package.24 Usually,
it is the S-enantiomers of AMPA analogues that possess
biological activity, whereas the R-enantiomers generally
fail to activate the receptor.10,25 The S-enantiomers of
2 and 5a-c were built in tri-ionized form, minimized,
conformationally searched using MMFFs/GB-SA, and
docked using Glide 3.5.24 The experimental binding
mode of (S)-2 was reproduced (rmsd ) 0.4 Å). All four
ligands could be docked into the closed binding domain
using Glide, although 5b and 5c only preferred the
binding mode of 2 when docked with scaled van der
Waals radii (factor 0.8), indicating that a degree of
domain opening would be required to accommodate
these ligands. The trends in the unscaled Emodel and
Glide scores were in good agreement with the biological
data, as follows: 2 (-165.4, -10.9); 5a (-145.2, -10.2);
5b (-108.2, -8.5); 5c (-84.7, -6.0).
Notably, while a rotamer of the propyl analogue 5b
in a 2-like binding mode is barely tolerated by close
approach to the hydrogen bonding network mediated
by Y732, the isopropyl analogue 5c cannot avoid clash-
ing sterically with M708 and E402 (Figure 2). The best
ranked complexes corresponding to (S)-2 were refined
with constrained minimization using impref in First
Discovery24 to allow for induced fit. The final complexes
are depicted in Figure 2. The propyl compound 5b seems
to lose affinity because of the energy penalty associated
with folding of the protein side chains into the required
conformation and the extra loss of conformational
entropy upon ligand binding. The complexes induced by
all four ligands are very similar, apart from the effect
of the isopropyl group of 5c. In order for this ligand to
bind, E402 would be forced to lengthen its hydrogen
bond to T686. This hydrogen bond is known as an
interdomain “lock”, present in all agonized complexes
of the GluR2 construct solved experimentally. Further-
more, M708 is pushed into a less favorable conforma-
tion, leading to decreased affinity, overall due to the
energetic cost of side chain perturbation. Thus, ligand
entropy, steric conflicts, and receptor conformational
energy penalties explain the marked loss in affinity over
the series, from methyl to ethyl, propyl, and isopropyl
analogues.
Data at Native iGluRsa
receptor binding
[3H]CGP electrophysiol
[3H]AMPA
IC50 (nM)
[3H]KA
IC50 (nM)
39653
cortical slice
EC50 (nM)
compd
Ki (nM)
(S)-1
21b
[19; 22]
54000
24000c,d
> 100000b 3800d
[22000; 27000]
>100000
3e
>100000
>100000
>100000
>100000
>1000000
(RS)-2f 27
>100000
330
110
nd
(S)-2f
9
>100000
4a
27000
>100000
[24000; 31000]
>100000
>100000
134
[126; 142]
2500
[2300; 2800]
6200
[5300; 7200]
4b
4c
5a
>100000
>100000
>100000
>100000
>100000
>100000
nd
nd
3500
[3200; 3800]
32000
[31000; 33000]
71000
[67000; 75000]
5b
5c
>100000
>100000
>100000
>100000
a Values are expressed as the antilog to the log of the mean of
at least three individual experiments. The numbers in brackets
[min; max] indicate (SEM according to a logarithmic distribution
c
of IC50 or Ki. b Reference 27. Bmax1 was 20%. d Reference 28.
e Reference 9. f Reference 10.
is more shielded in the 1-isomers (144 ppm) than in the
corresponding 2-isomers (155-156 ppm) in accordance
with previous reports.15,16
In Vitro Pharmacology. The binding affinities of
4a-c and 5a-c for the three classes of native iGluRs
were tested using the radioligands [3H]AMPA,17
[3H]KA,18 and [3H]CGP 3965319 (NMDA receptors) in a
binding assay using a rat brain synaptosomal prepara-
tion20 (Table 1). Like the 2-methyltetrazolyl isomer
(RS)-2,9 the 2-isomers of the ethyl, propyl, and isopropyl
analogues 5a-c showed affinity for [3H]AMPA binding
sites, whereas the corresponding 1-isomers 4a-c had
no significant affinity. Affinity for the [3H]KA or
[3H]CGP 39653 binding sites was insignificant or could
not be detected for any of the substituted tetrazolyl
analogues. The affinity for the [3H]AMPA binding site
decreased with increasing steric bulk of the tetrazolyl
substituent. Thus, the 2-ethyl analogue 5a showed 5
times weaker affinity than (RS)-2,9 whereas the 2-propyl
and 2-isopropyl analogues (5b and 5c) displayed a
pronounced loss of affinity, being 2 orders of magnitude
weaker than (RS)-2.
A modified version21 of the previously described rat
cortical wedge preparation22 was used as an in vitro
electrophysiological model to evaluate the activity of the
compounds at native iGluRs (Table 1). As with (RS)-2,9
the 2-substituted alkyltetrazolyl analogues (5a-c) were
AMPA receptor agonists. (S)-2 and compounds 5a-c
were further characterized using cloned homomeric
AMPA and KA receptors expressed in Sf9 insect cells23
(Table 2). In general, the order of potencies detected in
the binding to native receptors and the cortical wedge
assays was also observed in this assay; affinity de-
creases with increasing substituent size. Although the
compounds did not bind detectably to native KA receptor
sites (Table 1), they showed affinity for the cloned
homomeric GluR5 KA receptor sites (Table 2).
Discussion
Different structural analogues of AMPA have been
synthesized,1 and introduction of the alanine moiety on
the heterocyclic structure has required multiple syn-
thetic steps with low overall yields, involving protecting
groups that frequently require harsh conditions for
deprotection. Several methods were examined as at-
tempts to overcome these difficulties. For example,
various palladium-catalyzed reactions such as the Heck
reaction and Negishi and Suzuki coupling reactions
employing alanine synthons were tried with limited
success. The unexpected observation that lithiation of
the 4-position of the heterocycle in 9 was possible
encouraged us to attempt conjugate addition of the
Grignard reagent of 9 to methyl 2-acetaminoacrylate
because similar reactions with alkyl and benzyl Grig-
nard reagents have previously been reported.26 Since
Molecular Modeling. The structural basis for the
decreased AMPA receptor affinity with increasing steric
bulk of the 2-tetrazolyl substituent was examined by
flexibly docking the global minima of 5a-c to the
domain-closed extracellular binding construct of GluR2,

Brief Articles
Table 2. Receptor Binding Affinity at Cloned Subtypes Expressed in Sf9 Cellsa
receptor affinity (Ki in nM)
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3441
compd
GluR1
GluR2
GluR3
GluR4
GluR5
GluR6
1
21.9 ( 4.4
5.22 ( 0.36
145 ( 15
5150 ( 1020
10000 ( 2550
16.8 ( 2.9
3.89 ( 0.85
80.2 ( 5.9
1610 ( 470
2930 ( 960
20.6 ( 2.6
2.24 ( 0.09
44.8 ( 10.3
1180 ( 192
3710 ( 811
40.0 ( 19.9
2.70 ( 0.30
44.4 ( 3.4
732 ( 131
2350 ( 243
1150 ( 114
81.0 ( 3.0
2920 ( 364
5450 ( 670
34200 ( 1160
>1000000
18800 ( 3660
>100000
(S)-2
5a
5b
5c
>100000
>100000
a Mean ( SD from at least three experiments.
acid-labile groups into the 4-position of the 3-alkoxy-
isoxazole ring, which greatly facilitates the synthesis
of a series of alkyl tetrazolyl-AMPA analogues. 1-Sub-
stituted tetrazole derivatives 4a-c were inactive,
whereas the agonist potencies of the corresponding
2-isomers 5a-c decreased with increasing size of the
alkyl substituent. The structural basis for this order of
potency was apparent when the novel ligands were
docked into the ligand binding domain of GluR2.
Experimental Section
4-Iodo-3-isopropoxyisoxazole-5-carbonitrile (16). Com-
pound 9 (152 mg, 1.0 mmol) was dissolved in dry THF (4 mL)
and cooled to -78 °C. n-BuLi (1.6 M, 625 µL) was slowly added,
resulting in a dark-red color. The solution was stirred for
20 min, and iodine (305 mg, 1.2 mmol) dissolved in dry THF
(0.5 mL) was added. The mixture was stirred and slowly
warmed to -20 °C over 4 h, and the reaction was quenched
with saturated NH4Cl. Water (20 mL) was added and extracted
with Et2O (3 × 20 mL). The combined organic phase was
washed with aqueous Na2SO3 (20%, 2 × 10 mL) and dried
(MgSO4), and the solvent was removed in vacuo to give 16
(190 mg, 68%) as white crystals.
tert-Butyl (RS)-2-(N,N-Di-tert-butoxycarbonylamino)-
3-(5-cyano-3-isopropoxy-4-isoxazolyl)propionate (18). To
a stirred solution of 9 (188 mg, 1.24 mmol) in dry THF (3 mL)
at -78 °C was added n-BuLi (811 µL, 1.6 M) over 5 min. The
dark-red solution was stirred for 20 min and slowly warmed
to -60 °C. Compound 17 (467 mg, 1.36 mmol) dissolved in dry
THF (0.5 mL) was added slowly over 40 min. The solution was
stirred at -50 to -40 °C for 5 h. The solution was quenched
with saturated NH4Cl (20 mL), and the aqueous phase was
extracted with EtOAc (4 × 20 mL). The combined organic
phase was dried (MgSO4), and the solvent was removed in
vacuo. Flash chromatography (FC) (pentane/EtOAc 8:1) gave
18 (275 mg, 45%) as white crystals: mp 91-94 °C. Anal.
(C24H37N3O8) C, H, N.
tert-Butyl (RS)-2-(N,N-Di-tert-butoxycarbonylamino)-
3-[3-isopropoxy-5-(1H-5-tetrazolyl)-4-isoxazolyl]propi-
onate (19). Sodium azide (97 mg, 1.49 mmol) and triethyl-
amine hydrochloride (205 mg, 1.49 mmol) were added to a
solution of 18 (616 mg, 1.24 mmol) in dry DME (4 mL). The
suspension was stirred at 90 °C for 48 h. The reaction mixture
was cooled to room temperature (rt), the solvent was removed
in vacuo, water (25 mL) was added, and pH was adjusted to
10 with NaOH (2 M). The aqueous phase was extracted with
Et2O (3 × 20 mL). The aqueous phase was acidified to
pH ) 2 with aqueous KHSO4 (1 M), which resulted in white
precipitation, and was then extracted with EtOAc (4 × 25 mL).
The combined EtOAc phase was dried (MgSO4) and the solvent
was removed in vacuo to give 19 (554 mg, 83%) as white
crystals. A sample was recrystallized (toluene): mp 136-
138 °C. Anal. (C24H38N6O8) C, H, N.
tert-Butyl (RS)-2-(N,N-Di-tert-butoxycarbonylamino)-
3-[3-isopropoxy-5-(1-ethyl-1H-5-tetrazolyl)-4-isoxazolyl]-
propionate (21a) and tert-Butyl (RS)-2-(N,N-Di-tert-
butoxycarbonylamino)-3-[3-isopropoxy-5-(2-ethyl-2H-5-
tetrazolyl)-4-isoxazolyl]propionate (22a). Potassium -
carbonate (278 mg, 2.00 mmol) was added to a solution of 19
(540 mg, 1.00 mmol) in acetone (2.0 mL). The suspension was
stirred for 15 min, and ethyl iodide (244 µL, 3.02 mmol) was
added. The suspension was stirred at room temperature for
Figure 2. (S)-2 (colored by atom type), (S)-5a (cyan), (S)-5b
(purple), and (S)-5c (orange) docked to GluR2S1S2. While
2-ethyl and 2-propyl groups can be accommodated with minor
alterations in the binding mode compared to (S)-2, the iso-
propyl group of (S)-5c cannot avoid steric clashes with E402
and M708.
no reaction was observed, we tried different protecting
motifs and metals. Dehydroalanine containing two Boc
groups and a tert-butyl ester (17) proved to be an
effective substrate for lithiated 9 (Scheme 2). The two
Boc groups prevent deprotonation of the amide, enhance
the electrophilicity of the alkene, and enable the re-
moval of all protecting groups in one step. This reaction
constitutes a method for coupling of the entire alanine
moiety to the heterocycle in a single step in gratifying
yield. Introduction of the amino acid moiety at this stage
made a short and convergent synthesis possible, where
the alkyl substituents on the tetrazole ring are intro-
duced immediately before deprotection.
According to the X-ray structure of (S)-2 cocrystallized
with the receptor binding pocket of GluR2,6 the
2-methyltetrazolyl substituent seems to fit perfectly into
a partly hydrophobic and partly hydrophilic pocket, and
therefore, a loss of affinity could be expected if the
pocket has to accommodate larger substituents. Indeed,
pharmacological characterization of 5a-c in binding
affinity and functional electrophysiological assays shows
that affinity and agonist potency of the compounds
decrease as the size of the substituent on the tetrazole
ring increases. Docking to the receptor illuminates this
trend, since the ethyl analogue can be easily docked,
whereas propyl and especially isopropyl substitutents
can only be accommodated by forcing the side chains in
the receptor pocket to rearrange (Figure 2).
In conclusion, we have developed a method for the
introduction of an alanine side chain protected with

3442 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
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16 h. The solvent was removed in vacuo, and the residue was
dissolved in water (20 mL). The aqueous phase was extracted
with EtOAc (4 × 20 mL), the combined organic phases were
washed with brine (10 mL) and dried (MgSO4), and the solvent
was removed in vacuo to afford a colorless oil. According to
1H NMR a 1:2 mixture of the 1-isomer 21a and 2-isomer 22a
was obtained. FC (pentane/EtOAc 6:1) gave 21a (85 mg, 15%)
and 22a (318 mg, 56%) as colorless oils.
(RS)-2-Amino-3-[3-hydroxy-5-(2-ethyl-2H-5-tetrazolyl)-
4-isoxazolyl]propionic Acid (5a). The experimental proce-
dure was according to Scheme 2. A solution of 22a (333 mg,
0.59 mmol) in aqueous HBr (48%, 2 mL) was refluxed in a
preheated 140 °C oil bath for 20 min. The solution was cooled,
the solvent was removed in vacuo, and the residue was
evaporated with water (3 × 5 mL). The residue was purified
by reversed-phase HPLC and recrystallized (water) to give 5a
(115 mg, 73%) as white crystals: mp >220 °C. Anal. (C9H12N6O4)
C, H, N.
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Acknowledgment. This work was supported by
grants from the Lundbeck Foundation and the Novo
Nordisk Foundation.
Supporting Information Available: NMR for all com-
pounds, experimental procedures for 4, 5, 7-10, 12-15, 17,
and 20-23, and experimental details for pharmacology and
molecular modeling. This material is available free of charge
via the Internet at http://pubs.acs.org.
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