In recent years, there has been increasing evidence that serotonergic neurotransmission modulates a wide variety of experimentally induced seizures. Generally, agents that elevate extracellular serotonin (5-HT) levels, such as 5-hydroxytryptophan and serotonin reuptake blockers, inhibit both focal and generalized seizures, although exceptions have been described, too. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions. Furthermore, it has been shown that several anti-epileptic drugs increase endogenous extracellular 5-HT concentration. 5-HT receptors are expressed in almost all networks involved in epilepsies. Currently, the role of at least 5-HT 1A , 5-HT 2C , 5-HT 3 and 5-HT 7 receptor subtypes in epileptogenesis and/or propagation has been described. Mutant mice lacking 5-HT 1A or 5-HT 2C receptors show increased seizure activity and/or lower threshold. In general, hyperpolarization of glutamatergic neurons by 5-HT 1A receptors and depolarization of GABAergic neurons by 5-HT 2C receptors as well as antagonists of 5-HT 3 and 5-HT 7 receptors decrease the excitability in most, but not all, networks involved in epilepsies. Imaging data and analysis of resected tissue of epileptic patients, and studies in animal models all provide evidence that endogenous 5-HT, the activity of its receptors, and pharmaceuticals with serotonin agonist and/or antagonist properties play a significant role in the pathogenesis of epilepsies.

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The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the �- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/μ= 269 and δ/μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).