hapter12 Principles of Pharmacodynamics and Medical Chemistry vol.3

Chapter12 今日のメモ☆

第三回目の項はStructural Features[構造特性] & Pharmacologic activity[薬理活性]。

Nonspecific drugs[構造非特異的薬物]
 - nonspecific drugs : drug molecule's physical characteristics > chemical structure
    physical characteristics : cell membrane's lipid nature & drug's lipid attraction
    ex)anesthetics[麻酔薬]、 hyponotics[睡眠薬]、bactericidal agents[殺菌剤]

Structurally specific[構造特異的薬物]
 - specific drugs : drug's ability to bind to a specific endogenous receptor.
    * Receptor-site theory[受容体部位説]
        The lock-and-key theory
          : complementary relationshiop[補完関係]、Not conformational change[立体構造変化]
        Induced-fit theory
          : complementary relationship、mutual conformational changes ex) allosteric inhibitors
        Ocupational theory of responce
          : proportional[比例する] to the number of receptors occupied by the drug

    * Receptor-site binding[受容体部位結合]
        ability to bind to a specific receptor (its binding ability, exactness of its fit to the receptor)
        critical portion[臨界量] of the drug moleculeが関与(Not entire drug molecure)
        pharmacophore[活性基] : critical portionを作っているfunctional group[官能基]
        similar critical regions have similar qualitative 薬理学的反応を示す
        the better a drug fits to the receptor site, the higher the affinity and the geater response.
        agonist[作動剤] & antagonist[阻害剤]

Stereochemistry[立体異性体]
 - Optical isomer[光学異性体]
    asymmetric or chiral carbon[不斉炭素]を１つ以上含む
    * Enantiomers[鏡像異性体]
        dextrorotatory[右旋性](D/+) : clockwise
        levorotatory[左旋性](L/－) : counterclockwise
    * racemic mixture[ラセミ混合物] : D:L=1:1, optically inactive
        鏡像異性体は、potency, receptor fit, biological activity, transport, metabolismが異なる。
        ex) lovorphanol : narcotic[麻薬性]、analgestic[鎮痛性]、antitussive[鎮咳]作用有
        ex) dextorphanol : only antitussive作用
    * Diastereomers[ジアステレオマー]
        at least two chiral centers、光学異性体のうち鏡像異性体でないもの
        それぞれのジアステレオマーは、solubility, colatility[揮発度], melting pointにおいて異なる
    * Epimers[エピマー]
        special type of diastereomers
        one chiral centerのみの立体は一が異なる化合物のこと
        ex) α-glucose & β-glucose

 - Geometric isomers[幾何学異性体]
    * Cis-trans isomers[シス－トランス異性体]
        biological properties & pharmacologic activityが異なる
        ex) cic-diethylstil-bestrol & trans-dietylstilbestrol

 - Conformational isomers[配座異性体](rotamer[回転異性体])
        ex) trans conformation of acetylcholine－musucarinic receptor
        ex) gauche conformation of it－nicotinic receptor      
    *Bioisosteres[生物学的等価体]
       spatially[空間的に] & electronically equivalentのため、interchangeable[互換性]がある
       isosteric replacement : potency↑, side effect↓, duration of action↑
       isosteric analogs[類似体] : act antagonistically[阻害作用]を表す
       ex) procainamide(-O- ⇒ -NH-) : amide(longer duration than procaine)
       ex) alloxanthine(isostere of xanthine) : inhibitor of xanthine oxidase


Today's question
- Stereochemistry(立体異性体)の問題
Q: All of the following statements about a structually specific agonist are true except which one?
(A) Activity is determined more by its chemical structure than by its physical properties.
(B) The entire molecule is involved in binding to a specific endogenous receptor.
(C) The drug cannot act unless it is first bound to a receptor.
(D) A minor structural change in a pharmacophore can produce a loss in activity.
(E) The higher the affinity between the drug and its receptor, the greater the biological response.





A: (B)
The binding of drug to its receptor usually involves only specific functional group.  These groups make up what is known as the pharmacophore of the drug molecule.  Although the entire drug molecule is present at the receptor site, only a portion of it, the pharmacophore, is required for a biological response.