Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Pyrethrum plant derived material or plant derived rotenone...
Patent
1996-02-21
2000-07-11
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Pyrethrum plant derived material or plant derived rotenone...
514649, 514651, 514655, 546139, 546141, 546149, 546164, 546176, 564342, 564344, 564345, 564381, 564383, A01N 6500, A01N 3302, C07C22100, C07D21700
Patent
active
060873469
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention is in the field of medicinal chemistry. In particular, the invention relates to new compounds having high binding to the sigma receptor and pharmaceutical compositions thereof. These compounds are useful for the treatment of central nervous system disorders, neurological disorders and other conditions.
BACKGROUND OF THE INVENTION
Brain sigma receptors are the subject of intense investigation in light of the fact that sigma receptors bind many psychotropic drugs (Sonders et al., Trends Neurosci., 1: 37-40 (1988)). Moreover, certain sigma receptor ligands have antipsychotic activity which suggests that sigma receptor active compounds may be used for the treatment of schizophrenia (Largent et al., Eur. J. Pharmacol., 11: 345-347 (1988)).
Certain neuroleptic (i.e., antipsychotic) agents bind with very high affinity at sigma sites. Su, T., J. Pharmacol. Exp. Ther., 223: 284 (1982); Tam, S. W., Proc. Nat. Acad. Sci (USA), 80: 6703 (1983). One agent with very high affinity for sigma sites (Ki ca 1 nM; i.e., approximately 100-fold higher affinity than N-allyl normetazocine (NANM) is the neuroleptic agent haloperidol. Tam, S. W., et al., Proc. Nat. Acad. Sci (USA), 81: 5618 (1984). Sigma-opiates, such as NANM, bind with low affinity at typical opiate receptors but bind with significant affinity at PCP receptors.
Current neuroleptic agents are thought to produce their effects via a dopaminergic (DA) mechanism; they display very high affinities for DA binding sites. However, not all of the potent neuroleptic agents bind at [.sup.3 H]NANM-labelled sigma sites, nor do the sigma-opiates bind at DA sites. This has led to the suggestion that the sites labelled by [.sup.3 H]NANM be termed sigma-sites and not sigma-opiate sites (i.e., it may simply be coincidental that the sigma opiates possess an opiate-like chemical structure). In addition, there has been speculation that agents with high affinity for sigma sites may either (a) produce psychotic effects (if they behave as agonists), or (b) produce antipsychotic effects (if they behave as antagonists). It has further been speculated that certain neuroleptic agents, such as haloperidol, produce their antipsychotic effects by both a sigma and DA mechanism. Tam, S. W. and Cook, L., Proc. Nat. Acad. Sci. (USA), 81: 5618 (1984). In fact, [.sup.3 H]haloperidol, in combination with spiperone (an agent with high affinity for DA sites and essentially no affinity for sigma sites) is now commonly used to label sigma sites in radioligand binding studies.
A number of researchers have studied the structure-activity relationship of sigma ligands. For example, Manallack, D. T., et al., Eur. J. Pharmacol., 144: 231-235 (1987), disclose a receptor model for the phencyclidine and sigma binding sites. Manallack et al. disclose that in a recent SAR study (Largent et al., in press), sigma site affinity was shown to be enhanced by large N-alkyl substituents, e.g., benzyl or phenylethyl.
Largent, B. L., et al., Mol. Pharmacol., 32: 772-784 (1987), disclose a study of the structural determinants of sigma receptor affinity. In particular, Largent et al. teach that several piperidine and piperazine derivatives have sigma receptor activity. Largent et al. also disclose that affinity for the sigma receptor is markedly influenced by the N-alkyl substituents, with more lipophilic substituents affording greater affinity for the sigma receptor binding sites.
Sharkey, J., et al., Eur. J. Pharmacol., 149: 171-174 (1988), studied the sigma receptor binding activity of cocaine-related compounds.
The literature contains a number of suggestions that the sigma receptor is not a single, homogeneous binding site. Bowen, W. D. et al., Eur. J. Pharm., 163: 309-318 (1989), disclose that the effect of U.V. radiation on sigma receptor binding depended on the radioligand used to assay for it. It was also demonstrated that the binding characteristics of several sigma ligands were different in membranes from certain cell lines than in guinea pig brain membranes. (Hellewell, S. B. a
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Fischer James B.
Glennon Richard A.
Cambridge NeuroScience, Inc.
Corless Peter F.
Covington Raymond
Kight John
O'Day Christine C.
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