Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-05
2004-07-13
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S278000, C540S522000, C540S543000, C546S016000, C546S018000
Reexamination Certificate
active
06762177
ABSTRACT:
BACKGROUND OF THE INVENTION
In 1976, Martin et al. (
J. Pharmacol. Exp. Ther.
1976, 197, 517-32) postulated that sigma receptors account for the actions of (+/−)-SKF 10,047 (N-allyl-normetazocine) and related racemic benzomorphans. These compounds produce a spectrum of behaviors in the dog referred to as canine delirium and have psychotomimetic effects in humans. Great interest in the hypothesis of Martin et al. concerning sigma receptors led to intense scrutiny of (+/−)-SKF 10,047. Ten years of additional research revealed that (+/−)-SKF 10,047 binds to three types of receptors: (−)-SKF 10,047 binds primarily to mu and kappa opiate receptors; (+)-SKF 10,047 binds to PCP receptors and to a unique site that retains the designation sigma receptor (See Quirion et al.
Trends Neurosci.
1987, 10, 444-46). Sigma receptors have also been called haloperidol-sensitive sigma receptors, etorphine-inaccessible sigma receptors, and naloxone-inaccessible sigma receptors (See Walker et al.
Neurology
1988, 38, 961-65).
Sigma receptors were originally thought to be a type of opiate receptor, but two subsequent findings convincingly demonstrated that this characterization was incorrect: (a) whereas opiate receptors are enantioselective for the (−)-isomers of opium-derived narcotics, narcotic antagonists, and their congeners, sigma receptors are enantioselective for the (+)-isomers; and (b) naloxone is ineffective against both the in vivo and in vitro effects of sigma ligands. Therefore, it became clear that the sigma receptor is not a type of opiate receptor.
Initially, investigators asserted that sigma receptors were identical with PCP receptors, based on the displacement of [
3
H]PCP binding by the prototypic sigma ligand (+/−)-SKF 10,047. For this reason, sigma receptors were sometimes called “sigma opiate/PCP receptors”. However, the drug selectivity pattern of [
3
H](+)-SKF 10,047 differs from that of [
3
H]PCP, showing that these substances bind to different receptors. For example, antipsychotic drugs (such as haloperidol) potently displace [
3
H](+)-SKF 10,047 binding, but they are weak or inactive against [
3
H]PCP binding. Conversely, PCP is weak antagonist of [
3
H]haloperidol binding.
Sigma and PCP receptors may also be differentiated by their distinct anatomical distributions, because [
3
H](+)-SKF 10,047 and [
3
H]PCP-binding sites are concentrated in different brain areas. Tam pointed out additional differences between [
3
H]PCP binding and [
3
H](+)-SKF 10,047 binding: the sensitivity of [
3
H]PCP binding to sodium ions; and the low affinity and small stereoselectivity shown by PCP receptors toward (+)-SKF 10,047 and (+)-ethylketocyclazocine. These findings showed that [
3
H](+)-SKF 10,047 binds to two distinct sites: a haloperidol-sensitive site (subsequently called the sigma receptor) and a PCP-sensitive site, subsequently called the PCP receptor.
Radioligand-binding studies revealed that many antipsychotic drugs bind to sigma receptors with high affinity. Haloperidol is among the most potent inhibitors of [
3
H](+)-SKF 10,047 binding, having a K
i
of 4 nM (Itzhak, Y.
Life Sci.
1988, 42, 745-52). Other antipsychotic drugs that possess moderate (K
i
<1000 nM) to high potency include perphenazine, (−)-butaclamol, acetophenazine, trifluoperazine, molindone, pimozide, thioridazine, and chlorpromazine (Tam and Cook
Proc. Natl. Acad. Sci. USA
1984, 81, 5618-21). The connection between sigma receptors and antipsychotic drugs was further strengthened by the finding that [
3
H]haloperidol binding is strongly reduced by the sigma ligands (+)-SKF 10,047 (+)-pentazocine, and (+)-cyclazocine. In fact, the sigma ligand (+)-pentazocine displaces [
3
H]haloperidol from its binding sites in guinea pig brain about 10 times more potently than the dopamine ligand spiperone.
Furthermore, sigma receptors and kappa receptors have been shown to bind the same opiates. However, kappa receptors prefer one stereoisomer, and sigma receptors prefer the other. Whereas kappa opiate receptors bind (−)-benzomorphans, sigma receptors bind (+)-benzomorphans. Examples are (−)-SKF 10,047, (−)-pentazocine, and (−)-SKF 10,047, (−)-pentazocine, (−)-cyclazocine, and (−)-ethylketocyclazoine, which bind to kappa opiate receptors; their (+)-enantiomers bind to sigma receptors. Another example of this distiction is found with cis and trans isomers of U50,488. Whereas the trans isomers show preference for kappa opiate receptors, the cis isomers show preference for sigma receptors. Thus, in two chemically unrelated classes of compounds, different isomers show preference for kappa or sigma receptors. These results suggest a complimentarily between the topography of the binding sites of the kappa opiate and the sigma receptor.
Haloperidol exhibits its highest affinity to the sigma site, which is distinct from the classical opiate or phencyclidine sites. See Bartoszyk, G. D. et al.
CNS Drug Reviews
1996, 2, 175-94. Functional connections between sigma receptors and dopaminergic neurons in mesolimbic and cortical areas have been identified, and the involvement of sigma sites in the action of antipsychotic drugs has been shown in animal experiments. Further evidence for the significance of sigma sites in schizophrenia comes from investigations showing that benzomorphans cause symptoms that resemble schizophrenia in humans. Finally, several post-mortem studies have shown that the number of sigma binding sites in cortical and cerebellar regions is reduced in schizophrenic patients. Some attempts have been made to develop novel antipsychotic drugs with selective affinity for the sigma receptor that would not have the extrapyramidal side effects (EPS) common to the classic neuroleptics. Among these drugs, rimcazole initially has been shown to have some efficacy in humans. However, such drugs retain EPS potential, and selective sigma ligands have ultimately not shown convincing antipsychotic efficacy in clinical trials. Drugs with greater selectivity for sigma receptors, or subtypes thereof, or drugs with higher intrinsic activity hold promise, e.g., as antipsychotics.
Following the discovery that sigma receptors bind antipsychotic drugs came the expected interest in the possible clinical significance of sigma ligands. Here the question of which effects of antipsychotic drugs may be mediated by sigma receptors becomes the central focus. The high concentration of sigma receptors in the motor system immediately raised the issue of the motor side effects of antipsychotic drugs. Simultaneously, the antipsychotic activity of sigma-active drugs such as haloperidol, coupled with the sigma-activity of rimcazole (a putative antipsychotic), raised the important question of the possiblity of novel sigma-binding antipsychotic drugs.
Several attempts have been made to formulate models of the sigma receptor that can explain the SAR data for various classes of sigma ligands. Largent et al. (
Mol. Pharmacol.
1987, 32, 772-84) performed conformational calculations on a total of 10 compounds, which included phenothiazines and other structures, in an attempt to determine the interatomic distances between the N-(aromatic plane) and N-(polar function). The calculated energy-minimized conformations of (−)-cyclazocine, cis- and trans-clopenthixol, haloperidol, and (+)-dexclamol were found to match their X-ray crystal structure conformations. This study indicated several structural requirements for sigma binding. First, the primary pharmacophore at sigma sites appears to be the 3- or 4-phenylpiperidine moiety, which is present in most compounds showing high affinity for sigma receptors. Second, affinity is greatly influenced by large hydrophobic N-alkyl substituents. Third, compounds from many different
Hauske James R.
Persons Paul E.
Radeke Heike
Foley & Hoag LLP
Gordon Dana M.
Kifle Bruck
Sepracor Inc.
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