chemistry

1. BY
LAYATMIKA NAYAK
MPHARM
ROLL NO-MPC1837
DEPT OF PHARMACEUTICAL CHEMISTRY
COLLEGE OF PHARMACEUTICAL SCIENCES ,BERHAMPUR.

2.  IT MAY INCREASE OR DECREASE THE
POTENCY OF THE DRUG.
 IT MAY GIVE UNTOWARD SIDE EFFECTS
 EVEN RIGIDITY OR FLEXIBILITY OF THE
STRUCTURE COUNTS A LOT DURING
DRUG RECEPTOR INTERACTIONS.

3. oNONSUPERIMPOSABLE ORIENTATIONS OF
MOLECULES DUE TO FREE ROTATIONS
AROUND THE SINGLE BONDS.
oBASIC STRUCTURE,BOND LENGTH AND
BOND ANGLE REMAINS SAME.

4.  IT SHOULD POSSESS A SINGLE BOND and
shouldnot be present in the ring system.
 Neither of the atoms which are joined by this
single bond can contain three identical
substituents (e.g., three hydrogen atoms, three
methyl groups, etc.) or else rotation about the
bond will be irrevelant.
 Bound to a nonterminal heavy atom Excluded
from the count are amide C–N bonds because
of their high rotational energy barrier .

5. some conformational isomers for their free rotation around single bonds
RBN = 2

6. TAKING SIMPLEST
EXAMPLES
•IN ETHANE
STAGGERED IS THE
MOST STABLE
CONFORMER OR
ROTAMER WITH
LEAST POTENTIAL
ENERGY
•IN BUTANE ANTI IS
THE MOST STABLE
CONFORMER.

8. IMAGINE A DRUG
MOLECULE LIKE
ACETYLCHOLINE
HERE THE
ROTATIONS IS
POSSIBLE BETWEEN 4
AND 5.
TRANS CONFORMER
IS THE MOST STABLE
CONFORMER .

9.  KNOW THE DIFFERENCE BETWEEN A
PREFERRED CONFORMATIONS AND
ACTIVE CONFORMATIONS
 ADVANTAGES AND DISADVANTAGES OF
CONFORMATIONAL RESTRICTIONS.

10. •THOUGH INFINITE CONFORMERS ARE
POSSIBLE DUE TO FREE ROTATION AROUND
A SINGLE BOND.
•ALL CONFORMERS ARE NOT OF EQUAL
IMPORTANCE.
•IN 1936,KEMP AND PITZER DETERMINED
THAT
• ROTATIONS OF THE CONFORMER ARE DUE
TO SOME ENERGY BARRIER

11. •STERIC REPULSION
•ELECTRONIC INTERACTIONS AMONG THE GROUPS.
Conformations which minimize any repulsive
interactions and maximize all attractive interactions
are more energetically favorable than other conformations
and are said to be PREFERRED CONFORMATIONS.

12. Hence for acyclic compounds conformations where the
larger groups are staggered and separated by greater
distance are more energetically favorable than skew
conformer.

13. IF FORCE OF ATTRACTION COMPENSATE STERIC
REPULSION FOR EXAMPLE
Gauche Conformer is the most stable one due to
intramolecular hydrogen bonding.

14. LOOKING INTO THE STERIC CONCEPT IT CAN BE THE STAGGERED
ONE BUT BY SPECTROGRAPHIC ANALYSIS IT IS THE GAUCHE FORM
WHICH IS PREFERRED.
•DUE TO INTRAMOLECULAR ATTRACTION BETWEEN
QUATERNARY NITROGEN AND ESTER CARBONYL
OVERCOMES THE STERIC BARRIER AND STABILIZES IT.

15. CONSIDERATIONS OF BOTH STERIC AND
ELECTRONIC FACTORS IS REQUIRED.

16.  DRUG MOLECULE CONFORMER THAT
BINDS TO A RECEPTOR OR AN ENZYME.
 IT CONTAINS THE CORRECT SPATIAL
ARRANGEMENTS OF ALL ESSENTIAL
GROUPS REQUIRED FOR
PHARMACOLOGICAL EFFECT
 IT MAY NOT BE THE PREFERRED ONE.

17. •IN ACETYLCHOLINE GAUCHE MAY BE THE PREFERRED ONE BUT
TRANS CONFORMER IS USED FOR BINDING WITH MUSCARINIC
RECEPTOR .
•IN TACROLIMUS IT MUST UNDERGO CIS-TRANS ISOMERIZATION OF
THE AMIDE BOND TO BIND TO THE RECEPTOR.
•CYCLOSPORINE IS TURNED INSIDE OUT TO GET ACTIVE BOUND
CONFORMATION LIKE ITS PEPTIDE BOND ISOMERIZES FROM CIS TO
TRANS.
ABOVE EXAMPLES SHOWS
THAT DRUGS SHOULD BE
FLEXIBLE FOR BINDING TO
DRUG RECEPTORS .

18.  ACTIVE CONFORMATIONS BINDS TO THE
RECEPTORS WITH IDEAS LIKE
 INDUCED FIT THEORY OR ZIPPER
MECHANISM OF BINDING DRUGS.
 IN INDUCED FIT THEORY BY KOSHLAND
STATES THAT THERE IS A CHANGE IN THE
CONFORMATIONS OF THE RECEPTORS
FOR EFFECTIVE BINDING AND TO
PRODUCE A BIOLOGICAL RESPONSE.
 IT IS A DYNAMIC PROCESS WITH MUTUAL
MOLDING OF BOTH RECEPTOR AND
MOLECULE.

20. CONFORMATIONAL
RESTRICTION
LOCK A MOLECULE IN
DESIRED
CONFORMATIONS.
FOR AN EXAMPLE IF X
AND Y ARE TWO
GROUPS REQUIRED FOR
THERAPEUTIC
PURPOSE AND B AND C
ARE ACTIVE
CONFORMER THEN
RESTRICTION OF A
PARTICULAR
CONFORMATION IS
REQUIRED.

21. USED AS SPECIFIC AGONIST/ANATAGONIST FOR
RECEPTORS
IT CAN REDUCE UNECESSARY SIDE EFFECTS OF
THE DRUGS.
SINGLE DRUG MOLECULE CAN PROVIDE
DIFFERENT EFFECTS IN THEIR DISTINCT
CONFORMERS.
INCREASED DURATION OF ACTION

22. THEREFORE A CONFORMATIONALLY ACTIVE
MOLECULE WITH ALL REQUIRED GROUPS IN
PROPER ORIENTATION HAVE HIGH AFFINITY FOR
THE RECEPTORS.

23. INTRODUCTION OF A DOUBLE BOND
E.g chlorpromazine produces antipsychotic
affects by blocking dopamine receptors.
THE ACTIVE CONFORMER IS THAT IN
WHICH THE NITROGEN IS LOCATED IN THE
CHLORINE CONTAINING AROMATIC RING.
SIDECHAIN IS FLEXIBLE AND NO OF
CONFORMERS ARE POSSIBLE,

24. INTRODUCTION OF
A DOUBLE BOND
GIVES RISE TO
THIOXANTHENE
(chlorprothixene)CLASS
OF DERIVATIVES
WITH E AND Z
ISOMERS.
FURTHER THE
REQUIRED
BIOACTIVE
CONFORMER IS THE
Z ISOMER THAN E.

25.  PROVIDES MORE RESTRICTION
 RING CLOSURE MECHANISM TO CHANGE
ACTIVITY OF A PROFILE.
 E.g AMPHETAMINE IS A POTENT CNS
STIMULANT.
TRANYLCYPROMINE IS A POTENT MAO
INHIBITOR
AFTER RING CLOSURE TRANYLCYPROMINE
IS 5000 TIMES MORE POTENT MAO
INHIBITOR THEN AMPHETAMINE.

26. Phenmetrazine is a cyclic analog of ephedrine. While
Ephedrine a conformationaly flexible molecule, is an
indirect acting adrenergic agonist with CNS stimulating
activity,phenmetrazine a conformationaly restricted
molecule, retains the activity of ephedrine without
pronounced CNS stimulation.

27.  THE DIRECTION IN WHICH THE RING IS
CLOSED MAY GIVE RISE TO CIS –TRANS
ISOMER
 THE EXTENT OF RESTRICTION IMPOSED
BY THE CLOSURE

28. CONFORMATIONAL ANALYSIS IS A
REQUIRED PARAMETER TO DETERMINE
THE ACTIVITY OF DRUG MOLECULES. A
BRIEF IDEA ABOUT THESE IS REQUIRED
DURING CHEMICAL DESIGN OF NEW
COMPOUNDS.

29.  American Journal of Pharmaceutical
Education Vol. 60, Summer 1996
 J. Pharm. Pharmac., 1967, 19, 561-589
 FOYE PRINCIPLES OF MEDICINAL
CHEMISTRY
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 Conformations Topic in wikkipedia