a phenylpiperidine that has many congeneric analogs. Fentanyl (3.15) is designed along
similar lines and has some tremendously active analogs, such as sufentanil. Even in the
methadone (3.16) molecule, the remnants of the piperidine ring are discernible. On the
basis of these and other analogs, the opiate pharmacophore consists of:
- A nonbonding N electron pair
- A phenyl ring, three carbons removed from the N
- A quaternary carbon, next to the phenyl ring
Basically, the same criteria apply to the enkephalins.
The addition of bulky substituents to a drug molecule often results in the emergence of
antagonists, since it permits the utilization of auxiliary binding sites on the receptor. This
trend is especially noticeable among the neurotransmitters. For example, the anticholiner-
gics,β-adrenergic blocking agents, and some serotonin antagonists show this correlation.
Large substituents often prevent enzymatic attack on a drug, thereby prolonging its
useful life. This technique was used to impart resistance to β-lactamase to the semi-
synthetic penicillins. The need for the proximity of the phenyl group to the lactam is
quite interesting: phenylbenzyl penicillin (8–26) is inactive as an enzyme inhibitor
because the phenyl group no longer hinders access of the enzyme to the lactam bond.
3.4.1.5 Physicochemical Alterations
Alteration of the physicochemical characteristics within a drug series is, of course, a result
of structural modification; it is just our point of view that changes. It is rather difficult
to change only a single parameter with any specific modification, with the potential
138 MEDICINAL CHEMISTRY