Relationship of three-dimensional structure of muscarinic antagonists to antimuscarinic activity: structure of thiodeacylaprophen hydrochloride.
C20H28NS+.Cl-, 2-(diethylamino)ethyl 1,1-diphenylethyl sulfide hydrochloride (thiodeacylaprophen hydrochloride), M(r) = 349.9, orthorhombic, P2(1)2(1)2(1), a = 8.933 (2), b = 11.710 (3), c = 18.934 (4) A, V = 1980.6 (7) A3, Z = 4, Dx = 1.173 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 26.70 cm-1, F(000) = 752, room temperature, final R = 4.1% for 1417 reflections with /Fo/ greater than 3 sigma (F). Thiodeacylaprophen crystallized as a tertiary amine hydrochloride salt. The S--C--C--N+ segment adopts a trans configuration as does one of the Cphenyl--C--S--C segments. A comparison of the structure of thiodeacylaprophen with the crystal structures of potent antimuscarinic agents suggests that the relatively weak antimuscarinic activity of thiodeacylaprophen compared to atropine and aprophen may be substantially due to the short intramolecular S...N+ distance of 4.106 (6) A. Other contributing structural factors may include the direction of the N+--H bond and restricted accessibility of the sulfur atom for interatomic interactions.
Karle
J M
JM
Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Karle
I L
IL
Gordon
R K
RK
Chiang
P K
PK
D000818:Animals; D004048:Diethylamines / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology; D014961:X-Ray Diffraction
D004048:Diethylamines; D010276:Parasympatholytics; D013440:Sulfides; C076464:thiodeacylaprophen