Jul 25, 1990 - Molecular structures of both compounds were obtained using single .... and Vercauteren, D. P. (1989)KEMIT, A Molecular Graphics System.
Journal of Crystallographic and Spectroscopic Research, Vol. 21, No. 4, 1991
Contributions of crystal structures, molecular electrostatic potential maps, and lipophilicity data to structure-activity relationships of some conformationally restricted nortropane benzamide neuroleptics Sonia Collin, 1'2 Alain Patiny, 1 Daniel P. Vercauteren, *'1 Bernadette Norberg, 1 Guy Evrard, 1 and Francois Durant I
Received July 25, 1990
Structural, electronic, and lipophilicity characteristics of dihydro-2,3-methoxy-4 and dihydro2,3[(phenylmethyl)-8 aza-8 bicyclo[3.2.1.] octyl-3]-2 1H -isoindolone-1, (exo), two conformationally restricted nortropane benzamide derivatives (subgroup of neuroleptic drugs) have been determined and compared to other more "flexible" analogs in order to explain their pharmacological antidopaminergic D2 activities. Molecular structures of both compounds were obtained using single crystal X-ray crystallography; molecular electrostatic potential maps were computed at the ab initio MO STO-3G level, and the capacity factors were measured by RP-HPLC.
Introduction
ularly that an intrabenzamidic hydrogen bond between the amidic nitrogen and the ortho methoxy group is required (Fig. 1). This particular geometry allows the basic nitrogen lone pair of the nortropane (pharmacophoric element 1) to be parallel to the phenyl ring (pharmacophoric element 2) and antiparallel to the carbonyl group (pharmacophoric element 3) (Collin et al., 1989e). To complete these results, two conformationally restricted (or "semi-rigid," i.e., the phenyl ring and the carbonyl group are in the same plane) analogs, dihydro2,3-methoxy-4 and dihydro-2,3[(phenylmethyl)-8 aza-8 bicyclo[3.2.1.] octyl-3]-2 1H -isoindolone-1, (exo), (Fig. 1, I and II) will be considered herein. Although not so potent as tropapride (i.e., lower affinity), these two drugs present a similar pharmacological profile (i.e., same activity) (Table 1). The affinity for the D2 receptor is evaluated from ability of the compounds to compete with apomorphine in the intraperitoneal climbing test on mice (EDso) (Dostert et al., 1982). We have shown that this in vivo test (Rumigny et al., 1984 is correlated to the [3H]spiperone in vitro activity with a correlation coefficient of 0.8 for 23 compounds (Collin et al., 1989a). The results of this i.p. climbing test are, more-
Substituted benzamides are atypical neuroleptic drugs used for treating neurological and psychotic disorders. Precisely, they act as selective antagonists on dopamine D2 receptors (Jenner and Marsden, 1979; Seeman, 1980) and display a Na+-dependent binding (Theodorou et al., 1980). Among the substituted benzamides, tropapride (Fig. 1) associating the orthopramide and nortropane fragments has been shown to be a very potent drug (Collin et al., 1987b; Durant et al., 1986; Jalfre et al., 1983). Starting from crystal coordinates, several attempts were made to identify the functional groups which are likely to be involved in receptor binding (Collinet al., 1986, 1989e; van de Waterbeemd and Testa, 1983). These conformational studies have shown partic-
~Laboratoire de Chimie Mol6culaire Stmcturale, FacultEs Universitaires Notre-Dame de la Paix, Rue de Bruxelles 61, B-5000 Namur, Belgium. 2present address: Unit6 de Brasserie et des Industries Alimentaires, Universit6 Catholique de Louvain, Place Croix du Sud 3, B-1348 Louvain-la-Neuve, Belgium.
431 0277-8068/91/0800-0431506.50/09 1991 PlenumPublishingCorporation
432
Collin, Patiny, Vercauteren, Norberg, Evrard, and Durant pharmacophoricelement 1
CH3
"O
CH3
Experimental and computational
/ All compounds were obtained from Delalande Research Centre (Rueil-Malmaison, France). X-ray diffraction
0 pl~'macophoric element 2 ~
Compounds I and II crystallized at room temperature from a solution of acetonitrile and acetonitrile/acetone, respectively. The main crystallographic data and structure determination conditions are provided in Table 2. X-ray intensities were corrected for Lorentz and polarization effects. Both structures were solved by direct methods (Sheldrick, 1976); the best FOM E maps revealed all the non-hydrogen atoms. The structures
I
pharmacophoric element 3
osCll~ compound I
I~
N
N
~
Table 2. Crystallographic data and instrumental settings
II
I
compound II O Fig. 1. Ptanar structure formulae of tropapride (with reference to the pharmacophoric elements described by Collin et al. (1989e) and "semi-rigid" analogs I and II,
over, well correlated to the i.p. hypothermial test (r = 0.95 for 38 compounds; Dostert et al., 1984). First, the three-dimensional structures solved by X-ray crystallography of single crystals of the two "semi-rigid" compounds will be compared with tropapride in order to verify that all three proposed pharmacophoric elements are present and similarly oriented. Second, as reported earlier for other D2 antagonists (Collin et al., 1989b; van de Waterbeemd et al., 1986), the recognition and binding to the receptor site will be approached by analyses of molecular electrostatic potential (MEP) iso-contour maps performed at the ab initio LCAO-MO-SCF level. Third, using the ReversePhase High Performance Liquid Chromatography technique (RP-HPLC), we will take into account their lipophilicity in order to explain the observed activity variations as compared to tropapride. Table 1, Antidopaminergic activities (climbing i.p., p EDs0), dissociation constants (pKa), capacity factors (log kw), and extrapolated capacity factors (log k~)
Tropapride Compound I Compound II
p EDso
pK,
log kw
log k,~
2.00 -0.48 0.10
8.91 8.68 8.71
1.881 2.960 2.418
3.308 4.168 3.654
Molecular formula Molecular weight Crystal system Space group a (~.) b (A) c (A) /3 (o) V (,~3) Z D x (g cm 3) Temperature (K) Crystal dimension (mm) Radiation Diffractometer Absorption coefficient (cm- ~) F(O00) 20 range/deg Unique data
C~3HzoN202 9HCI
Cz2H24N20. HC1
398.9 monoclinic
368.9 monoclinic
P2~/c
P2Jn
13.551(1) 10.431(6) 15.400(3) 112.54(1) 2010.17 4 1.32 293 0.32, 0.23, 0.03
18.926(1) 15.910(1) 6.311(1) 93.86(1) 1895.98 4 1.29 293 0.32, 0.27, 0.10
Graphite monochromated Cu Kc~, ~ = 1.54178 Enraf-Nonius CAD-4 17.43 17.73
848 780 4-144 4-144 6277 ( - 1 6
