opioid

It has been apparent for centuries that opium (e.g., heroin) derivatives such as morphine are powerful analgesics. Animal studies in the 1900s showed that a variety of brain regions are susceptible to the action of opiate drugs, particularily the periaqueductal gray matter and the rostral ventral medulla. There are also opiate-sensitive regions at the level of the spinal cord. In other words -- the areas that produce analgesia when stimulated are also responsive to exogenous opiates.

The analgesic action of opiates implied the existence of specific brain receptors for those drugs long before the receptors were actually found (which happened in the sixties and seventies. Since it's unlikely that those receptors evolved to respond to the administration of opium, scientists started to believe that there must be endogenous compounds for which the receptors had evolved. Several categories of endogenous opiods have been isolated from the brain.

Endogenous Opioids

Leucine-enkephalin

Tyr-Gly-Gly-Phe-Leu-OH

Methionine-enkephalin

Tyr-Gly-Gly-Phe-Met-OH

β-Endorphin

Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Val-Lys-Asn-Ala-His-Lys-Gly-Gln-OH

α-Neoendorphin

Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys

Dynorphin

Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Gln-OH

Neuroscience, Sinaur Associates (QP355.2.N487 1997)

The structure of morphine was worked out in 1925 by English chemist Sir Robert Robinson. He was also responsible for working out the structure of strychnine in 1946.

                     
                         
             C == C    C - N - CH3
            /      \   :  /
      HO - C        C -:-C
            \      /   :  \
             C -- C ...C   C
             |     \      /
             |      C == C
             |     /      \
             O -- C       C
                   \\    //
                    C -- C
                   /
                 HO

                Morphine

The C₅-N-CH₃ ring structure in morphine is called a piperidine. The ring formed by oxygen and the four carbons is called a furan.

   OH                  
   |                      
   C = O     C == C    C - N - CH3
   |        /      \   :  /
   CH2-O - C        C -:-C
            \      /   :  \
             C -- C ...C   C
             |     \      /
             |      C == C
             |     /      \
             O -- C       C
                   \\    //
                    C -- C
                   /
                  O
                   \
                    CH2 - C = O
                          |
                          OH
                Heroin (3,6-diacetylmorphine)

                     
                         
             C == C    C - N - CH3
            /      \   :  /
      HO - C        C -:-C 
            \      /   :  \
             C -- C ...C   C
             |     \      /
             |      C == C
             |     /      \
             O -- C       C
                   \\    //
                    C -- C
                   /
                  O
                   \
                    CH3
                Codeine (Methylmorphine)

Morphine -OH 
Heroin   -2(OCH2COOH)
Codeine  -OCH3

We can see from the structures of heroin and codeine above how altering one or two functional groups on the morphine molecule vastly affect its activity.

Work has been done on the structure of morphine for years, with the aim of increasing its activity and at the same time reducing its addictive properties. The molecules produced in this fashion are called synthetic morphine analogues.

One incredibly successful synthetic morphine analogue is (-)levorphanol.

               
             C == C    C - N - CH3
            /      \   :  /
           C        C -:-C
            \\    //   :  \
             C -- C ...C   C
                   \      /
                    C == C
                   /      \
                  C       C
                   \\    //
                    C -- C
                   /
                 HO
                  
                  Levorphanol

Eliminating the furan (the oxygen "bridge") from morphine, creates compounds called Morphinans, such as Levorphanol, which is five to six times more active than morphine.

Perhaps the most successful group of synthetic morphine analogues has been the piperidine derivatives. They represent the ultimate simplification of the morphine skeleton. They were first developed in the 1940's and one, meperidine (Demerol) is perhaps the most widely used synthetic opiate in clinical practice despite its addictive properties.

                     C - N - CH3
                     |   |
          C == C     C   C
         /      \    |   |
        C        C - C - C
         \\    //    |
          C -- C     C = O
                     |
                     O
                     C2H5

          Meperidine (Demerol)