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The validity of a parameter, which represents the direction of the molecular dipole vector of phencyclidine (PCP) derivatives, was reviewed. This parameter, named DVDP, quantitatively predicted the receptor binding activity of various PCP analogues. DVDP also effectively explained the activity of remarkably different compounds such as the MK-801 derivatives. For the comparison of the dipole direction, the arrangement of the molecules was investigated by superimposition. The molecules were superimposed on hypothetical receptor points that were assumed on the characteristic pharmacophores of centrally acting drugs. However, for the MK-801 derivatives, the superimposition based on the steric overlapping volume and the electrostatic repulsion was dominant. The study confirmed the importance of the hydrocarbon portion of the PCP piperidine ring and suggested an opposite orientation of MK-801 to the conventional 3-point model.

Quantitative structure-activity relationship analysis has been acoomplished on 24 derivatives of phencyclidine (PCP). By analysis with conceivable parameters effecting the variation of activity, it was shown that a compound with a smaller dipole moment, larger hydrophobicity, and a smaller principal moment of inertia is a stronger ligand of the receptor.By furthe examination of this fact, the direction of the dipole vector of the ligand molecule was demonstrated to be important for the activity. Consequently, an equation, which sufficiently explains the variation of the activity, was derived using the difference in direction of the dipole vector as the only parameter. This is the first quantitative analysis explanning the variation of activity of PCP derivatives.

Quantitative Structure-Activity Relationships (QSAR) of inhibitors of dopamine (DA)- and norepinephrine (NE)-uptake have been analyzed quantitatively. Previously, we reported that several series of congeners are susceptible to similar substituent effects, and these structurally diverse compounds interact with common receptor points by the hydrophobic interaction of a phenyl group and the hydrogen bonding of a nitrogen atom. In this report, we extended this concept to derive an equation that quantitatively interprets the activity of 113 compounds comprising 6 skeletal groups. Excellent QSAR equations were obtained in which all parameters used were physicochemically significant. Of the parameters adopted therein, the root mean square (rms) of the distances between corresponding pharmacophore was an especially valuable parameter to compare the activity of the structurally diverse compounds. On the other hand, a substituent existing in a specific region of the inhibitor molecule causes steric hindrance with the receptor and interferes with an effective binding of the inhibitor. Lastly, it was concluded that a degree of correspondence of proper pharmacophore to the receptor points, as well as the volume of that specific region, principally determines the binding ability of that congener, and the substituent effect of each compound is added to that fundamental affinity.

Quantitative structure-activity relationship (QSAR) analysis of 3-phenyl-1-indanamines, 1-amino-4-aryltetralins, and 6-phenylpyrrolo[2,1-a] isoquinolines has been performed for catecholamine-uptake inhibition activities. Similar equations were obtained for these series of congeners indicating a common tendency that the increase in hydrophobicity of the substituents on the primary phenyl ring (ring C) enhances the activity, and the important aromatic ring which interacts with the receptor is this ring C. It was also indicated that the effect of the introduction of the second N-methyl group differs depending on the series of congeners. These results were used to characterize a binding model for a pharmacophore, which comprised a phenyl ring and a basic nitrogen. This model defined the necessary three-dimensional features leading to the uptake inhibition, and degree of fitness with this model predicted the strength of the activity. Furthermore, it appeared likely that a substituent existing in a specific region of the inhibitor molecule causes a steric hindrance with the receptor site and reduces the activity.

SDDSの50倍散を市販の配合飼料に混じ,各群2匹の子豚に,薬剤実景それぞれ1.25mg,2.5mg,5.0mg,10.0mg/kg/dayを朝夕2回に分けて投与し続けた.薬剤投与後8日目に,トキソプラブマ原虫(自然感染豚より分離し,マウスにて継代中の)TT株の腹腔内感染(マウス腹腔内増殖型虫体5×106/pig),または経口感染(感染マウス2匹/pig)を実施した.その後,感染無投薬対照豚の発症が軽度であったので,経口感染群では,4日後にふたたび感染マウス2匹/pigを餌食せしめた.さらに10日後に眼結膜感染(5×106/pig)を行ない,腹腔内感染群では,28日後に,前報4)で使用したHG株の再接種(2×107/Pig)を試みた.その結果,1.25mg/kg/dayの投薬量でも,経口感染に対して抵抗を示し,発熱も,パラジテミアも完全に阻止された.一方,腹腔内感染群では,2.5mg,5.0mg,10.0mg/kg/day各群とも,完全に発病が阻止された.ただしバラジテミアは10.0mg/kglday群の1例に1回観察されたが,その他の供試豚では,すべて陰性を示した.試験豚計12例を,初回トキソプラズマ感染後60~74日の間に殺処分し,体内の諸臓器,リンパ節,筋肉等における原虫の存否を検索した.その結果,投薬群は全例陰性であったのに比し,対照群の半数では,心筋,横隔膜,肋間筋または脳から,原虫が検出された.以上の成績から,SDDS散剤の経口投与は,豚トキソプラズマ症感染防御にきわめて有効であることが認められた.