The treatment of chronic and non-chronic states of pain is of great importance in medicine. There is a worldwide need for pain therapies which are highly effective. The urgent need for action for targeted treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient, is documented in the large number of scientific works which have been published recently in the field of applied analgesics and of basic research into nociception.
Conventional μ-opioids, such as morphine, have a good action in the therapy of severe to very severe pain and are of very great importance for pain therapy. However, it may be of advantage if, in addition to the μ-opioid receptor, other opioid receptors, in particular the ORL1 receptor, are influenced since pure μ-opioids also have undesirable side effects, such as constipation and respiratory depression, and can also lead to dependency. The δ, κ and ORL1 opioid receptors are also involved in the pain event (Opioids: Introduction, p. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).
It is moreover known that influencing of the reuptake of serotonin and/or noradrenaline can have a favourable effect on the action spectrum and spectrum of side effects of opioids (example: tramadol, cf. Opioids with Clinical Relevance: Tramadol, 228-230 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH 2002).
The ORL1 receptor is moreover also involved in regulation of further physiological and pathophysiological processes. These include, inter alia, learning and memory development (Manabe et al., Nature, 394, 1997, p. 577-581), audition (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and numerous further processes. A review article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays a role or with high probability could play a role. There are mentioned, inter alia: analgesia, stimulation and regulation of food intake, influence on μ-agonists, such as morphine, treatment of withdrawal symptoms, reduction in the addiction potential of opioids, anxiolysis, modulation of movement activity, memory impairments, epilepsy; modulation of neurotransmitter secretion, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is also discussed.
Structurally related compounds which have an affinity for the ORL1 receptor are known from the prior art (WO 02090317). No influence on the reuptake of noradrenaline and serotonin has hitherto been described for this structure class.