William T. Jorgensen

The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats.

Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V1aR) pharmacology and regional patterns of c‐Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus‐maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c‐Fos expression. Results showed that WAY 267,464 had higher affinity (Ki) at the V1aR than the OTR (113 versus 978 nm). However, it had no functional response at the V1aR and only a weak functional effect (EC50) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V1aR antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V1aR (503 nm), with a functional EC50 of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V1aR agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c‐Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c‐Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V1aR. Antagonism of the V1aR by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences.

Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity

A series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ(1) and σ(2) receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (4, σ(1)K(i)=27 nM, σ(2)K(i)=55 nM) showed reduced affinity for D(1)-D(5) dopamine receptors when compared to haloperidol itself. The compound with the greatest σ(1) affinity in the series, benzamide 4 (σ(1)K(i)=7.6 nM, σ(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ(2) selective parent benzamide, RHM-2 (3, σ(1)K(i)=10412 nM, σ(2)K(i)=13.3 nM).

Trishomocubane as a scaffold for the development of selective dopamine transporter (DAT) ligands

In our continued exploration of trishomocubane derivatives with central nervous system (CNS) activity, N-arylalkyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (10-13) displaying affinity for the sigma (σ) receptor were also found, in several cases, to interact with the dopamine transporter (DAT). Compound 12 was identified as the first trishomocubane-derived high affinity DAT ligand (K(i) = 1.2 nM), with greater than 8300-fold selectivity over the monoamine transporters NET and SERT, and only low to moderate affinity for σ(1) and σ(2) receptors.

The Formation of Seven-Membered Heterocycles under Mild Pictet–Spengler Conditions: A Route to Pyrazolo[3,4]benzodiazepines

Reported is a method for the synthesis of seven-membered heterocycles via a Pictet-Spengler condensation reaction under very mild conditions. High substrate scope allows for use of aldehydes using catalytic amounts of acetic acid yielding 39-90% and ketones using catalytic amounts of trifluoroacetic acid yielding 25-83%.

Investigation of pyrazolo-sulfonamides as putative small molecule oxytocin receptor agonists

The neuropeptide oxytocin has been implicated in multiple central nervous system functions in mammalian species. Increased levels have been reported to improve trust, alleviate symptoms related to autism and social phobias, and reduce social anxiety. Hoffman-La Roche published a patent claiming to have found potent small molecule oxytocin receptor agonists, smaller than the first non-peptide oxytocin agonist reported, WAY 267,464. We selected two of the more potent compounds from the patent and, in addition, created WAY 267,464 hybrid structures and determined their oxytocin and vasopressin receptor activity. Human embryonic kidney and Chinese hamster ovary cells were used for the expression of oxytocin or vasopressin 1a receptors and activity assessed via IP1 accumulation assays and calcium FLIPR assays. The results concluded that the reported compounds in the patent and the hybrid structures have no activity at the oxytocin or vasopressin 1a receptors.