organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
Holt, 1995, 1996a). (ii) The B ring should be in a pseudo-axial
position relative to the ¯oor of the boat. (iii) Rings A and B
should display an orthogonal relationship. (iv) Electron-
withdrawing substituents on the B ring improve activity in
the order o>m>>p. (v) Substituents on the B ring should be in
the `prow' position and not projecting backwards over the B
ring. Furthermore, the conformation of the carbonyl groups of
the ester moieties at C3 and C5 of ring A may be either ap
or sp relative to the near double bond of the DHP ring
(Scheme).
The conformation of a molecule in the crystal structure
does not represent a priori the conformation of the molecule
in its receptor site. The environment in the crystalline solid
is surely different from that of the molecule in its receptor
site. However, the process of crystallization, of maximizing
hydrogen bonding, dipole±dipole and van der Waals type
interactions within the solid must mimic the behavior of a
molecule approaching its docking site. Both are processes of
molecular recognition. Thus it is worthwhile to examine
patterns of molecular interaction in the crystal as a guide to
what to expect of the docked molecule. Particularly useful
to this end are examinations of series of structures
containing similar B ring substituents because they offer
multiple observations of the molecule adapting to its envir-
onment. We have synthesized three DHP molecules with
multiple methoxy groups substituted on the B ring: (I), (II)
and (III).
ISSN 0108-2701
Three methoxy-substituted diethyl
4-phenyl-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate
compounds
Sara K. Metcalf and Elizabeth M. Holt*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078,
USA
Correspondence e-mail: betsy@biochem.okstate.edu
Received 29 October 1999
Accepted 27 July 2000
Diethyl 4-(2,5-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate, C21H27NO6, (I), diethyl 4-(3,4-
dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-di-
carboxylate, C21H27NO6, (II), and diethyl 2,6-dimethyl-4-
(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxyl-
ate, C22H29NO7, (III), crystallize with hydrogen-bonding
networks involving the H atom bonded to the N atom of the
1,4-dihydropyridine ring and carbonyl O atoms in (I) and (II).
Unusually, (III) shows O atoms of methoxy groups serving as
hydrogen-bond acceptors.
Comment
1,4-Dihydropyridine compounds (DHPs) are widely
prescribed for treatment of hypertension and heart de®brila-
tion. Their activity is believed to arise from binding with a
receptor site located in the ꢀ1 subunit of the l-type voltage
gated channels present in skeletal and cardiac muscle (Tanabe
et al., 1987).
DHP molecules with methoxy substituents on the B ring are
not unknown in the literature. For example, the synthesis of
(II) has been reported (Shirodkar & Varadarajan, 1996;
Ohsumi et al., 1995). However, the solid-state structures of (I),
(II) and (III) are unreported. Previous work has shown that
esteri®cation groups should be small (Rowan & Holt, 1996b,
1997; Rowan, 1996) for optimum activity, thus we have
synthesized molecules with ethoxycarbonyl groups at C3 and
C5.
Compounds (I), (II) and (III) crystallize with the A rings
in ¯attened boat form. The sum of the absolute values of the
six successive torsional angles of the A ring may be used to
quantify the ¯atness of these rings, the total being zero if the
ring is totally ¯at and 240ꢁ if the six-membered ring is in classic
boat form. The sums of the absolute values of the torsion
angles for the A ring in (I), (II) and (III) are 91.0, 102.5 and
76.5ꢁ, respectively. Thus all three structures display signi®cant
¯attening of the boat conformation of the A ring.
Early molecular modeling work involving SYBYL (Tripos
Scienti®c, 1982) did not permit conformational ¯exibility of
the drug or the receptor site. A static molecule was ®tted into a
static receptor site. Newer software (FlexiDocK; Tripos
Scienti®c, 1998; GOLD; Jones et al., 1997) permits rotation
about speci®ed bonds of both drug and receptor site groups,
however, results using the newer programs do not agree with
each other nor do they support the results of docking studies
carried out with SYBYL. Thus, one seeks a knowledge of DHP
interactions with polar environments as a basis for evaluation
of the molecular modeling results. For DHP molecules (see
Scheme), structure±activity relationship studies (Triggle et al.,
1989) have indicated speci®c conformational details which
correlate with high binding ef®ciency. (i) The A ring should be
in a ¯attened boat form (the total planarity achieved by
making ring A aromatic is detrimental to activity; Rowan &
ꢀ
1228 # 2000 International Union of Crystallography Printed in Great Britain ± all rights reserved
Acta Cryst. (2000). C56, 1228±1231
Metcalf, Sara K.
