Structural comparison of the potent antimuscarinic agent azaprophen hydrochloride with aprophen hydrochloride and structurally related antimuscarinic agents.
A comparison of the crystalline structure of the potent azaprophen with the crystalline structures of aprophen and four other structurally related antimuscarinic agents reveals the potential for an ionic interaction of the cationic nitrogen atom and the carbonyl oxygen atom with the muscarinic receptor and an aromatic interaction with a phenyl group. 6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate hydrochloride (azaprophen hydrochloride), C23H28NO2+.Cl-, Mr = 385.9, monoclinic, P2(1)/c, a = 8.490 (1), b = 14.335 (2), c = 16.847 (2) A, beta = 93.63 (1) degree, V = 2046.2 A3, Z = 4, Dx = 1.253 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 17.86 cm-1, F(000) = 824, room temperature, final R = 4.25% for 2460 reflections with [Fo[ greater than 3 sigma. 2-Diethylaminoethyl 2,2-diphenylpropionate hydrochloride (aprophen hydrochloride), C21H28NO2+.Cl-, Mr = 361.9, orthorhombic, Pbca, a = 15.118 (3), b = 7.488 (2), c = 36.306 (10) A, V = 4110.8 A3, Z = 8, Dx = 1.316 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 17.45 cm-1, F(000) = 1552, room temperature, final R = 7.96% for 1846 reflections with [Fo[ greater than 3 sigma. Both azaprophen and aprophen were crystallized as tertiary amine salts. The overall conformation of both molecules is similar as demonstrated by space-filling models and superimposed stick drawings. Although the interatomic distance between the nitrogen atom and the carbonyl oxygen atom of azaprophen and aprophen is comparable at 5.41 and 5.07 A, respectively, the nitrogen atoms of azaprophen and aprophen are 1.16 A apart when the acyloxy portion (--O--C = O) of both molecules is superimposed. A conformational analysis of azaprophen, aprophen and the structurally similar antimuscarinic agents reveals a buried ether oxygen atom and an exposed carbonyl oxygen atom as well as the common placement of a phenyl group on the same side of the acyloxy plane as the cationic nitrogen atom.(ABSTRACT TRUNCATED AT 250 WORDS)
Karle
J M
JM
Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Karle
I L
IL
Chiang
P K
PK
D008958:Models, Molecular; D008968:Molecular Conformation; D010276:Parasympatholytics / Q000032:analysis*; D010666:Phenylpropionates / Q000032:analysis*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000032:analysis*; D014961:X-Ray Diffraction
D010276:Parasympatholytics; D010666:Phenylpropionates; D011976:Receptors, Muscarinic; D014326:Tropanes; C052339:azaprophen; C006615:aprofen