Local anesthetic compounds and uses

Details Local anesthetic compounds and uses Local anesthetic compounds and uses

2000-10-03

2003-06-10

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S532000, C514S534000, C514S616000, C560S039000, C560S043000, C560S044000

Reexamination Certificate

active

06576791

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel multibinding local anesthetic compounds that bind to voltage-gated Na
+
ion channels and thereby modulate their activity. The compounds of this invention comprise at least two ligands covalently connected by a linker or linkers, wherein at least one of the ligands in its monovalent (i.e., unlinked) state binds to and is capable of modulating the activity of a voltage-gated Na
+
ion channel. The ligands are linked together such that the multibinding compounds thus formed demonstrate a biologic and/or therapeutic effect on processes mediated by voltage-gated Na
+
ion channels that is greater than that of the same number of unlinked ligands made available for binding to the channels. In one preferred embodiment, the compounds of the present invention are capable of producing local anesthesia of longer duration than are the corresponding unlinked monovalent ligands. The invention also relates to methods of using such compounds and to methods of preparing them.
These multibinding local anesthetic compounds are particularly useful in treating conditions and diseases that require pain control. Accordingly, this invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an effective amount of a compound of this invention.
BACKGROUND
State of the Art
Action potentials are generated in nerve and muscle cells by ion currents that pass selectively across plasma membranes through transmembrane ion channels. Local anesthetics exert their effects by specifically binding to Na
+
channels, thereby inhibiting Na
+
currents and causing the blockade of Na
+
channel-dependent impulse conduction. The necessary practical advantage of local anesthetics is that their action is reversible at clinically relevant concentrations and their use is followed by complete recovery of nerve and muscle function with no evidence of damage to nerve fibers or cells.
Ion channels are formed by the association of integral membrane proteins into a structure having a central hydrophilic pore. The structure of the voltage-gated sodium ion channel has been extensively studied (reviewed by W A Catterall,
Annu. Rev. Biochem
. 64: 493-531 (1995)). The channel consists of a complex of one &agr;- and 2&bgr;-subunits.
FIG. 1A
illustrates the general features of the channel. The &agr;-subunit is the pore-forming subunit, contains a voltage sensor and contains specific binding sites for local anesthetic drugs. This subunit consists of a polypeptide chain with four homologous domains (I-IV), each domain comprising 6 membrane-spanning protein helices (S1-S6). This subunit is flanked at the outer surface of the membrane by two &bgr;-subunits, which are heavily glycosylated and which interact with the lipid bilayer in which the channel is embedded. The &bgr;
2
chain is topologically similar to the &bgr;
1
chain, but is not shown in the figure.
Ion channels are characterized by their gating and selectivity properties. Selectivity refers to the rate at which different ion species pass through an open channel under standard conditions. The Na
+
channel pore is selectively permeable to Na
+
, which passes through the channel at rates that are diffusion-limited, and which equilibrates according to the electrochemical gradient across the membrane. Gating is the process that regulates the opening and closing of an ion channel. The voltage-gated Na
+
channel opens and closes in response to changes in membrane potential. When the membrane is depolarized (i.e., the membrane potential becomes less negative ), the “resting” channel transitions through closed intermediate states to become an “open” Na
+
-conducting channel. With time, the channel closes and becomes “inactivated” (i.e., refractory to reopening ). The channel recovers its ability to respond to a depolarizing stimulus by returning to the “resting state” after an interval of time.
There is considerable evidence that the channel itself is a specific receptor for local anesthetics. As mentioned above, the Na
+
channel contains specific binding sites for local anesthetic drugs, which exhibit stereoselectivity.
FIG. 1B
shows a highly schematic representation of the Na
+
channel illustrating differences in the binding sites for different classes of Na
+
channel modulators and blocking agents, as is currently understood.
The binding sites for neurotoxins, such as saxatoxin and tetrodotoxin (TTX), and scorpion and anemone toxins (ScTx) are thought to be located at the outer mouth of the channel pore. This region includes binding sites for cations, e.g. ammonium ions, as well.
Other, more lipid soluble toxins, such as batrachotoxin (BTX), veratridine, and aconitine, bind within the channel and act to spontaneously open the channel and/or prevent it from closing normally. Current understanding of neuronal sodium channels indicates that binding sites for “classical” local anesthetics (LA), such as lidocaine, as well as lipophilic quaternary ammonium ion channel blockers, may lie within the internal region of the channel, as shown. This binding site is understood to be allosterically linked to the BTX binding site. Lipophilic binding domains are found at the innermost region of the channel.
It has been suggested that tertiary amine drugs may have two binding sites on the channel, a first site located near the pore that preferentially binds charged species and a second site that binds neutral species. The binding of an anesthetic molecule to the first site would block ion permeation through the pore, while the binding to the second site would act to prevent conformational changes that are required for channel opening (G R Strichartz, Chapter 2, In:
Neural Blockade in Clinical Anesthesia and Management of Pain, Third Edition
, (M J Cousins and P O Bridenbaugh, Eds.), Lippincott-Raven Publishers, Philadelphia(1998)).
The inhibitory effect of certain local anesthetics is enhanced by membrane depolarization. This effect is attributed to a higher affinity of these local anesthetics for inactivated channels than for resting channels. Repetitive depolarizations potentiate anesthetic activity by “use-dependent” (phasic) block such that an increasing number of channels become stabilized in the non-conducting state.
The duration of action of a local anesthetic is proportional to the time during which it is present at effective concentrations in contact with the nerve, or, more precisely, the ion channel(s). The effect of most currently used local anesthetics tends to be short-lived as a result of dissociation from and diffusion away from the intended site of action; therefore, repeated doses must be administered for a prolonged effect. Undesired side effects of local anesthetics are largely a function of systemic concentrations of the drug resulting from such diffusion. These effects include paralysis of cardiac and smooth muscle systems, or undesired stimulation of the CNS. Because of these serious side effects, the quantity of drug administered must be carefully controlled.
Consequently, local anesthetic compounds having properties that allow effective concentrations to be maintained at the intended local site of action would be useful for prolonging the duration of action, thereby enhancing the clinical utility of local anesthetics in pain management and mitigating untoward toxic effects resulting from systemic concentration of the drug.
SUMMARY OF THE INVENTION
This invention provides novel multibinding compounds that are useful as inhibitors of voltage-gated Na
+
channels and are effective as local anesthetics. Accordingly, one aspect of this invention is directed to multibinding compounds of Formula I:
(L)
p
(X)
q
  I
and pharmaceutically acceptable salts thereof; wherein:
each L is a ligand that may be the same or different at each occurrence;
each X is a linker that may be the same or different at each occurrence;
p is an integer of from 2 to 10; and
q is an integer of from 2 to 20;
 wherei

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